TBK1 is a kinase involved in innate immunity and autophagy pathways. Recent human genetics studies have linked mutations in TBK1 to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons. TBK1 plays a major role in autophagy by phosphorylating autophagy adaptor proteins, and several other ALS-linked genes are also involved in autophagy. Mutations in TBK1 may impair autophagy and contribute to the accumulation of protein aggregates, a hallmark of ALS pathology. The review discusses the role of TBK1 in autophagy and how disrupted autophagy may underlie the pathogenesis of ALS
Analisi di variazioni nucleotidiche in geni di gestione del ferro in pazienti...MerqurioEditore_redazione
This document summarizes the analysis of genetic variations in genes related to iron metabolism in patients with Parkinson's disease and other movement disorders. The researchers scanned several iron-related genes for mutations in patients with Parkinson's and neurodegeneration with brain iron accumulation. They identified several known and novel sequence variations in ceruloplasmin, iron regulatory protein 2, hemopexin, hepcidin, and hemojuvelin genes. However, none of the variations found were significantly associated with the movement disorders studied. The results suggest that iron metabolism genes may contribute to disease risk but specific variants in these genes do not have a major effect on susceptibility to Parkinson's and related disorders.
Hairy research: Can hair tell the story about your health?Firhan Malik
This document outlines a proposed thesis on analyzing metal exposure through hair samples. It discusses the roles of various metals like iron, zinc, arsenic, and nickel in the body. Zinc is important for immune function and deficiency can increase apoptosis of immune cells. Arsenic and nickel are carcinogenic and can negatively impact the immune system. Nickel specifically can activate genes like HIF-1 that promote tumor growth. The document proposes using hair samples to measure long-term metal exposure in people, as hair levels reflect chronic intake over months to years. Factors like hair color and sex can influence metal content measured in hair.
The document summarizes a webinar presentation about telomere shortening and its relationship to human disease and cancer. The presentation discusses how telomeres shorten with cell division, potentially leading to diseases like dyskeratosis congenita and acquired aplastic anemia. It shows that some patients with acquired aplastic anemia have mutations in the telomerase gene TERT that cause shorter telomeres, increased chromosomal instability, and worse outcomes. Telomere length may be a predictor of relapse and survival in aplastic anemia patients.
Learning and understanding the correlation between telomere shortening and disease is the most important principal to stop the aging process. Dr Sears is one of the worlds most respected and renown Anti-Aging physicians in the world. Please visit our website at www.alsearsmd.com or www.searwellnesscenter.com for tons of great free information.
Mutations are heritable changes in an organism's genetic material. They arise from errors in DNA replication or distribution and can cause sudden changes in characteristics. There are two main types of mutations - gene mutations, which alter the sequence of a single gene, and chromosomal mutations, which involve changes in chromosome number or structure. Point mutations specifically change a single DNA nucleotide, and can be further classified as transitions, transversions, nonsense, missense, or silent mutations depending on their effects. Frameshift mutations insert or delete DNA nucleotides, altering the reading frame and resulting in abnormal proteins. Many diseases like cystic fibrosis, sickle cell anemia, and cancer are caused by specific point or frameshift mutations.
This document discusses several types of genetic mutations and variations that can occur, including pseudogenes, transposons, expanding triplet repeats, and copy number variants. It provides examples of how each type can disrupt gene function and cause genetic disorders. The position and severity of a mutation depends on how it affects the protein encoded by the gene. The genetic code and certain mutations help lessen the effects of mutations by resulting in synonymous codons or similar amino acid substitutions. Conditional mutations only cause effects under certain environmental conditions.
Analisi di variazioni nucleotidiche in geni di gestione del ferro in pazienti...MerqurioEditore_redazione
This document summarizes the analysis of genetic variations in genes related to iron metabolism in patients with Parkinson's disease and other movement disorders. The researchers scanned several iron-related genes for mutations in patients with Parkinson's and neurodegeneration with brain iron accumulation. They identified several known and novel sequence variations in ceruloplasmin, iron regulatory protein 2, hemopexin, hepcidin, and hemojuvelin genes. However, none of the variations found were significantly associated with the movement disorders studied. The results suggest that iron metabolism genes may contribute to disease risk but specific variants in these genes do not have a major effect on susceptibility to Parkinson's and related disorders.
Hairy research: Can hair tell the story about your health?Firhan Malik
This document outlines a proposed thesis on analyzing metal exposure through hair samples. It discusses the roles of various metals like iron, zinc, arsenic, and nickel in the body. Zinc is important for immune function and deficiency can increase apoptosis of immune cells. Arsenic and nickel are carcinogenic and can negatively impact the immune system. Nickel specifically can activate genes like HIF-1 that promote tumor growth. The document proposes using hair samples to measure long-term metal exposure in people, as hair levels reflect chronic intake over months to years. Factors like hair color and sex can influence metal content measured in hair.
The document summarizes a webinar presentation about telomere shortening and its relationship to human disease and cancer. The presentation discusses how telomeres shorten with cell division, potentially leading to diseases like dyskeratosis congenita and acquired aplastic anemia. It shows that some patients with acquired aplastic anemia have mutations in the telomerase gene TERT that cause shorter telomeres, increased chromosomal instability, and worse outcomes. Telomere length may be a predictor of relapse and survival in aplastic anemia patients.
Learning and understanding the correlation between telomere shortening and disease is the most important principal to stop the aging process. Dr Sears is one of the worlds most respected and renown Anti-Aging physicians in the world. Please visit our website at www.alsearsmd.com or www.searwellnesscenter.com for tons of great free information.
Mutations are heritable changes in an organism's genetic material. They arise from errors in DNA replication or distribution and can cause sudden changes in characteristics. There are two main types of mutations - gene mutations, which alter the sequence of a single gene, and chromosomal mutations, which involve changes in chromosome number or structure. Point mutations specifically change a single DNA nucleotide, and can be further classified as transitions, transversions, nonsense, missense, or silent mutations depending on their effects. Frameshift mutations insert or delete DNA nucleotides, altering the reading frame and resulting in abnormal proteins. Many diseases like cystic fibrosis, sickle cell anemia, and cancer are caused by specific point or frameshift mutations.
This document discusses several types of genetic mutations and variations that can occur, including pseudogenes, transposons, expanding triplet repeats, and copy number variants. It provides examples of how each type can disrupt gene function and cause genetic disorders. The position and severity of a mutation depends on how it affects the protein encoded by the gene. The genetic code and certain mutations help lessen the effects of mutations by resulting in synonymous codons or similar amino acid substitutions. Conditional mutations only cause effects under certain environmental conditions.
This document summarizes Hannah Shapero's research project on the effects of a sut-2 mutation in Caenorhabditis elegans worms expressing human TDP-43. The research found that a point mutation in the sut-2 gene led to a partial amelioration of the uncoordinated phenotype seen in worms expressing human TDP-43 alone. This suggests the sut-2 mutation can suppress some of the toxic effects caused by TDP-43 protein aggregates, which are implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases.
This document summarizes research on CRP3/MLP (cysteine-rich protein 3/muscle LIM protein) and its role in vein graft failure and arterialization. It discusses how CRP3/MLP expression is normally present in arteries but absent in veins, but becomes upregulated in veins during adaptation to arterial hemodynamics. Studies in a CRP3/MLP knockout rat model showed it acts as a key modifier of vein remodeling by sensitizing stretched smooth muscle cells to apoptosis. The research suggests CRP3/MLP may be a new target to prevent neointimal growth and vein graft failure, and could help predict outcomes of vascular therapies.
This document summarizes a project investigating whether mitochondrial DNA-encoded oxidative phosphorylation (OXPHOS) transcripts are dysregulated in the blood of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to controls. The student researcher designed primers, conducted quantitative real-time PCR on blood samples from controls and patients, and found several mtDNA-encoded OXPHOS transcripts were significantly more abundant in MCI and AD patients. This suggests peripheral changes in mitochondrial gene expression occur early in AD and could provide biomarkers for early diagnosis and monitoring disease progression and treatment responses.
The Amerithrax investigation followed the 2001 anthrax attacks that killed 5 people. Letters containing anthrax spores were sent to media outlets and two senators. The FBI investigation into the source of the anthrax took 7 years.
Mutations are changes in DNA sequences that are present in less than 1% of a population. Mutations can range from single DNA base changes to missing or extra chromosomes. They can affect protein function and transcription. Most mutations are recessive and cause loss of function, while gain-of-function mutations tend to be dominant.
Sickle cell disease was the first genetic illness understood at the molecular level. It results from a single amino acid substitution in the beta globin protein that causes
Telomeres are protective caps on the ends of chromosomes that shorten with each cell division. When telomeres become too short, cells enter a permanent non-dividing state called replicative senescence. Telomerase is an enzyme that adds DNA repeats to telomeres to counteract their shortening. Telomerase is active in stem cells and early development but inactive in most adult tissues, leading to age-related telomere shortening. Shorter telomere length is associated with increased risk of aging, disease, and mortality. Lifestyle factors like exercise, stress reduction, and antioxidants may help slow telomere shortening. A small molecule called TA-65 was found to activate telomerase
Senior Sem. Final Project-Professional MaterialsMia Matthews
Resveratrol is a natural compound that may help reduce beta-amyloid plaques and prevent/treat Alzheimer's disease. It has shown to bind to amyloid proteins, changing their shape to non-toxic forms and decreasing their accumulation in the brain. Resveratrol also has antioxidant properties that can reduce oxidative stress associated with amyloid plaque formation. While studies in cells and animals have shown promise, more research is still needed to determine resveratrol's long-term safety and effectiveness in humans for treating Alzheimer's.
Telomeres, lifestyle, cancer, and agingHasnat Tariq
Telomeres are DNA-protein structures that protect chromosome ends from damage. Telomere length decreases with each cell division and critically short telomeres cause cell senescence or death. Certain lifestyle factors like smoking, obesity, stress, and diets low in antioxidants can accelerate telomere shortening and aging. Maintaining healthy habits like exercise, dietary restriction, and antioxidant-rich diets may help preserve telomeres and reduce cancer risk. Cancer cells maintain telomere length through high telomerase activity, making telomerase a potential target for cancer treatments.
It describes about Structure and function of telomere, Telomerase enzyme, How does telomerase works?, Telomere replication, What happens to telomeres as we age?, Factors contribute to telomere shortening
This document discusses gene mutations. It defines gene mutations as permanent alterations in DNA sequence that differ from what is typically found. Mutations can range in size from a single DNA base pair to a large chromosome segment. The document outlines several types of mutations including point mutations, insertion mutations, deletion mutations, and more. It explores how mutations can affect health and cause genetic disorders by altering protein function. Environmental factors and errors in DNA replication and transcription are presented as common causes of gene mutations.
This document summarizes various theories of aging biology. It discusses aging as the deterioration of physical functions over time. The maximum lifespan of different species is outlined. Key theories of aging include the wear and tear theory involving accumulation of damage over time, the genetic instability theory of mutations building up, and the oxidative damage theory involving reactive oxygen species. Other causes discussed are telomere shortening, mitochondrial DNA damage, programmed aging genes, gene silencing, caloric restriction, and the role of hormones like insulin. Multiple interacting factors influence the aging process.
Dr Una L Fairbrother
Telomere length: a 21st century biomarker" discusses DNA structure and the nature of telomeres. This talk explains the importance of telomere length and the impact of this feature on human health. The talk finishes describing the exciting work being carried out in London Metropolitan University to help develop this measure as a 21st century biomarker.
This document discusses mutations and various genetic blood disorders including sickle cell anemia, thalassemia, and anemia. It begins by defining mutation as a change in genetic material that can be caused by errors in DNA replication or repair. It then describes different types of mutations like substitutions, insertions, deletions, and frameshifts. The document outlines the molecular basis and effects of mutations like loss or gain of function. Sickle cell anemia is presented as a case study where a single point mutation causes the disease. Thalassemia and the differences between alpha and beta thalassemia are also summarized. The signs, symptoms, and treatments of various types of anemia conclude the document.
This document summarizes molecular mechanisms of mutation and DNA damage repair in cells. It discusses how mutagens can induce point mutations by substituting or damaging DNA bases, causing errors during DNA replication. It also describes genetic diseases linked to expansions of trinucleotide repeats, such as Fragile X syndrome and Huntington's disease. The document outlines several DNA repair pathways in cells and how defects in these pathways can lead to increased mutation rates and cancer-proneness.
This document discusses the central dogma of biology, which states that DNA is transcribed into RNA, which is then translated into protein. It describes the structures of DNA and RNA, the genetic code by which codons correspond to amino acids, and types of genetic alterations like mutations and chromosomal abnormalities. Mutations can be germline or somatic, and include substitutions, insertions, deletions, and frameshift mutations. Single nucleotide polymorphisms are also discussed.
Telomeres are repetitive DNA sequences at the ends of chromosomes that protect cellular DNA from degradation. Telomere shortening is linked to cellular aging and is thought to be a root cause of age-related diseases. Telomerase is an enzyme that adds telomere repeats to chromosome ends and counteracts telomere shortening during cell division. Studies have shown that activating telomerase can prolong cellular lifespan, rejuvenate cells, and delay age-related changes in animals. Preliminary studies in humans using TA-65, a molecule that activates telomerase, have shown benefits such as reduced levels of senescent immune cells and lengthened short telomeres without safety issues.
Biology unit 6 dna rna protein synthesis mutation notesrozeka01
Mutations are any changes in the sequence of nitrogenous bases in DNA. There are several types of mutations including missense, nonsense, silent, point, and frameshift mutations. Point mutations involve changing a single base through substitution, insertion, or deletion. Frameshift mutations are caused by insertions or deletions and shift the reading frame, altering the entire amino acid sequence.
How different diseases originate with slightest changes in proteins. Understanding ALS , Parkinson, Alzhiemer , Taupathies development which may lead to their treatment!
This document discusses epigenetics and provides an overview of key concepts. It begins with a brief history of epigenetics research from the 1940s to present day. It then defines epigenetics as the study of heritable alterations in gene expression that do not involve changes to DNA sequence. Several epigenetic mechanisms are identified, including DNA methylation, histone modification, and non-coding RNA. The document notes that epigenetic changes are involved in various diseases and disorders. It also discusses how environmental, behavioral, dietary, and psychological factors can influence epigenetics.
2014 Earth Rebirth Sooner Mosaic Social Justice Symposium PPAndrew Sartain
The 1st annual Sooner Mosaic Social Justice Symposium brought a large range of people to hear 24 chosen speakers on social justice issues. Earth Rebirth's presentation had one of the largest turnouts and some of the best feedback. Let's continue to dream big, act bigger.
www.earthrebirthnow.org
Prof. John Dernbach's presentaion on setting the agenda for environmental justice within legal education. Taken from the Environmental Justice in Legal Education event held at Warwick University on 29th March 2010.
This document summarizes Hannah Shapero's research project on the effects of a sut-2 mutation in Caenorhabditis elegans worms expressing human TDP-43. The research found that a point mutation in the sut-2 gene led to a partial amelioration of the uncoordinated phenotype seen in worms expressing human TDP-43 alone. This suggests the sut-2 mutation can suppress some of the toxic effects caused by TDP-43 protein aggregates, which are implicated in amyotrophic lateral sclerosis and other neurodegenerative diseases.
This document summarizes research on CRP3/MLP (cysteine-rich protein 3/muscle LIM protein) and its role in vein graft failure and arterialization. It discusses how CRP3/MLP expression is normally present in arteries but absent in veins, but becomes upregulated in veins during adaptation to arterial hemodynamics. Studies in a CRP3/MLP knockout rat model showed it acts as a key modifier of vein remodeling by sensitizing stretched smooth muscle cells to apoptosis. The research suggests CRP3/MLP may be a new target to prevent neointimal growth and vein graft failure, and could help predict outcomes of vascular therapies.
This document summarizes a project investigating whether mitochondrial DNA-encoded oxidative phosphorylation (OXPHOS) transcripts are dysregulated in the blood of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) compared to controls. The student researcher designed primers, conducted quantitative real-time PCR on blood samples from controls and patients, and found several mtDNA-encoded OXPHOS transcripts were significantly more abundant in MCI and AD patients. This suggests peripheral changes in mitochondrial gene expression occur early in AD and could provide biomarkers for early diagnosis and monitoring disease progression and treatment responses.
The Amerithrax investigation followed the 2001 anthrax attacks that killed 5 people. Letters containing anthrax spores were sent to media outlets and two senators. The FBI investigation into the source of the anthrax took 7 years.
Mutations are changes in DNA sequences that are present in less than 1% of a population. Mutations can range from single DNA base changes to missing or extra chromosomes. They can affect protein function and transcription. Most mutations are recessive and cause loss of function, while gain-of-function mutations tend to be dominant.
Sickle cell disease was the first genetic illness understood at the molecular level. It results from a single amino acid substitution in the beta globin protein that causes
Telomeres are protective caps on the ends of chromosomes that shorten with each cell division. When telomeres become too short, cells enter a permanent non-dividing state called replicative senescence. Telomerase is an enzyme that adds DNA repeats to telomeres to counteract their shortening. Telomerase is active in stem cells and early development but inactive in most adult tissues, leading to age-related telomere shortening. Shorter telomere length is associated with increased risk of aging, disease, and mortality. Lifestyle factors like exercise, stress reduction, and antioxidants may help slow telomere shortening. A small molecule called TA-65 was found to activate telomerase
Senior Sem. Final Project-Professional MaterialsMia Matthews
Resveratrol is a natural compound that may help reduce beta-amyloid plaques and prevent/treat Alzheimer's disease. It has shown to bind to amyloid proteins, changing their shape to non-toxic forms and decreasing their accumulation in the brain. Resveratrol also has antioxidant properties that can reduce oxidative stress associated with amyloid plaque formation. While studies in cells and animals have shown promise, more research is still needed to determine resveratrol's long-term safety and effectiveness in humans for treating Alzheimer's.
Telomeres, lifestyle, cancer, and agingHasnat Tariq
Telomeres are DNA-protein structures that protect chromosome ends from damage. Telomere length decreases with each cell division and critically short telomeres cause cell senescence or death. Certain lifestyle factors like smoking, obesity, stress, and diets low in antioxidants can accelerate telomere shortening and aging. Maintaining healthy habits like exercise, dietary restriction, and antioxidant-rich diets may help preserve telomeres and reduce cancer risk. Cancer cells maintain telomere length through high telomerase activity, making telomerase a potential target for cancer treatments.
It describes about Structure and function of telomere, Telomerase enzyme, How does telomerase works?, Telomere replication, What happens to telomeres as we age?, Factors contribute to telomere shortening
This document discusses gene mutations. It defines gene mutations as permanent alterations in DNA sequence that differ from what is typically found. Mutations can range in size from a single DNA base pair to a large chromosome segment. The document outlines several types of mutations including point mutations, insertion mutations, deletion mutations, and more. It explores how mutations can affect health and cause genetic disorders by altering protein function. Environmental factors and errors in DNA replication and transcription are presented as common causes of gene mutations.
This document summarizes various theories of aging biology. It discusses aging as the deterioration of physical functions over time. The maximum lifespan of different species is outlined. Key theories of aging include the wear and tear theory involving accumulation of damage over time, the genetic instability theory of mutations building up, and the oxidative damage theory involving reactive oxygen species. Other causes discussed are telomere shortening, mitochondrial DNA damage, programmed aging genes, gene silencing, caloric restriction, and the role of hormones like insulin. Multiple interacting factors influence the aging process.
Dr Una L Fairbrother
Telomere length: a 21st century biomarker" discusses DNA structure and the nature of telomeres. This talk explains the importance of telomere length and the impact of this feature on human health. The talk finishes describing the exciting work being carried out in London Metropolitan University to help develop this measure as a 21st century biomarker.
This document discusses mutations and various genetic blood disorders including sickle cell anemia, thalassemia, and anemia. It begins by defining mutation as a change in genetic material that can be caused by errors in DNA replication or repair. It then describes different types of mutations like substitutions, insertions, deletions, and frameshifts. The document outlines the molecular basis and effects of mutations like loss or gain of function. Sickle cell anemia is presented as a case study where a single point mutation causes the disease. Thalassemia and the differences between alpha and beta thalassemia are also summarized. The signs, symptoms, and treatments of various types of anemia conclude the document.
This document summarizes molecular mechanisms of mutation and DNA damage repair in cells. It discusses how mutagens can induce point mutations by substituting or damaging DNA bases, causing errors during DNA replication. It also describes genetic diseases linked to expansions of trinucleotide repeats, such as Fragile X syndrome and Huntington's disease. The document outlines several DNA repair pathways in cells and how defects in these pathways can lead to increased mutation rates and cancer-proneness.
This document discusses the central dogma of biology, which states that DNA is transcribed into RNA, which is then translated into protein. It describes the structures of DNA and RNA, the genetic code by which codons correspond to amino acids, and types of genetic alterations like mutations and chromosomal abnormalities. Mutations can be germline or somatic, and include substitutions, insertions, deletions, and frameshift mutations. Single nucleotide polymorphisms are also discussed.
Telomeres are repetitive DNA sequences at the ends of chromosomes that protect cellular DNA from degradation. Telomere shortening is linked to cellular aging and is thought to be a root cause of age-related diseases. Telomerase is an enzyme that adds telomere repeats to chromosome ends and counteracts telomere shortening during cell division. Studies have shown that activating telomerase can prolong cellular lifespan, rejuvenate cells, and delay age-related changes in animals. Preliminary studies in humans using TA-65, a molecule that activates telomerase, have shown benefits such as reduced levels of senescent immune cells and lengthened short telomeres without safety issues.
Biology unit 6 dna rna protein synthesis mutation notesrozeka01
Mutations are any changes in the sequence of nitrogenous bases in DNA. There are several types of mutations including missense, nonsense, silent, point, and frameshift mutations. Point mutations involve changing a single base through substitution, insertion, or deletion. Frameshift mutations are caused by insertions or deletions and shift the reading frame, altering the entire amino acid sequence.
How different diseases originate with slightest changes in proteins. Understanding ALS , Parkinson, Alzhiemer , Taupathies development which may lead to their treatment!
This document discusses epigenetics and provides an overview of key concepts. It begins with a brief history of epigenetics research from the 1940s to present day. It then defines epigenetics as the study of heritable alterations in gene expression that do not involve changes to DNA sequence. Several epigenetic mechanisms are identified, including DNA methylation, histone modification, and non-coding RNA. The document notes that epigenetic changes are involved in various diseases and disorders. It also discusses how environmental, behavioral, dietary, and psychological factors can influence epigenetics.
2014 Earth Rebirth Sooner Mosaic Social Justice Symposium PPAndrew Sartain
The 1st annual Sooner Mosaic Social Justice Symposium brought a large range of people to hear 24 chosen speakers on social justice issues. Earth Rebirth's presentation had one of the largest turnouts and some of the best feedback. Let's continue to dream big, act bigger.
www.earthrebirthnow.org
Prof. John Dernbach's presentaion on setting the agenda for environmental justice within legal education. Taken from the Environmental Justice in Legal Education event held at Warwick University on 29th March 2010.
Teaching Sustainability and Social Justice: A Resource for High School Teache...John W. Eppensteiner III
This document provides an overview of a 15-lesson syllabus for a high school course on sustainability and social justice. The course aims to impart an understanding of current and future environmental issues and their implications for human health and well-being. Each lesson includes a topic overview, learning objectives, assignments, and resources. Students will complete a capstone project to demonstrate their understanding of course themes and promote sustainability in their community.
Metropolis and Cisco publication providing an overview of what some of the most insightful cities have been doing over the last few years to address climate change with concrete solutions.
These span Metropolis member cities, those in the Connected Urban Development program, and other proactive and innovative cities across the world.
This document discusses environmental ethics and provides definitions of key concepts. It begins by stating that ethics are important for development and societies without ethical principles can experience moral decay. It then defines concepts like values, morals, environment, ecology, ecosystem, and different perspectives on environmental ethics like anthropocentrism, biocentrism, and ecocentrism. The document examines environmental ethics as the application of ethical standards to human relationships with the environment and poses example ethical dilemmas. It explores expanding ethical consideration to include animals, communities, and nature. In closing, it recommends developing a holistic perspective that preserves ecological connections.
The document discusses different approaches to environmental ethics, including anthropocentric, biocentric, ecocentric, and stewardship views. It provides examples of prominent thinkers who developed each approach, such as Aldo Leopold's land ethic and Arne Naess' deep ecology philosophy which argues that all life has intrinsic worth. The document also examines perspectives on humanity's relationship to the environment from frontier ethics, Judeo-Christian traditions, ecofeminism, and environmentalist Christianity.
Motor neuron disease (MND) refers to conditions characterized by degeneration of upper and lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of MND and involves both upper and lower motor neurons. ALS is defined clinically based on involvement of these motor neurons and leads to loss of muscle strength, atrophy, fasciculations, and difficulties with movement. The only approved treatment for ALS is riluzole, which may modestly extend survival by 2-3 months by reducing glutamate-induced excitotoxicity.
This study investigated apoptosis in a transgenic mouse model of ALS. The researchers found:
1) DNA fragmentation, a marker of apoptosis, was significantly higher in the brain regions of mice expressing a mutant SOD1 gene compared to control mice, as shown by TUNEL staining and ELISA assays.
2) Double staining showed many TUNEL-positive motoneurons and glial cells in the spinal cord and brainstem of mutant SOD1 mice, but not controls.
3) Electron microscopy confirmed neuronal and glial apoptosis in these regions through characteristic morphological features in mutant SOD1 mice.
4) TUNEL-positive neurons were also observed in the motor and sensory cortices of mutant
The Main Molecular Bases of Amyotrophic Lateral Sclerosis: An Integrating Reviewasclepiuspdfs
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects the lower and upper motor neurons. Its etiology is unknown, despite several studies that point to risk factors and genetic for the disease. It does not have a definitive treatment and the diagnosis, most of the time, is time consuming and demands varied criteria for adequate definition and classification. In the search for new treatments, gene therapy with gene insertion aims to reduce the impact of ALS on the patient. The study of molecular basis as the root cause of the disease becomes necessary to advance the discovery of effective treatment and a rapid diagnosis, aiming at improving the quality of life of the ALS patients. Therefore, the present work had the objective to bring an update of the literature on ALS, as well as to describe the main molecular bases involved in the causative/causative process of this disease.
The document summarizes research on the genetics and molecular mechanisms of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). It discusses how mutations in genes like C9orf72, SOD1, TARDBP, FUS, MAPT and GRN contribute to motor neuron death by disrupting RNA processing and transport. Protein aggregates like TDP-43 are found in patients, and liquid-liquid phase transitions may play a role in aggregate formation. Dysregulation of RNA-binding proteins and their interaction networks are implicated in disease pathogenesis.
A mitochondrion (singular of mitochondria) is part of every cell in the body that contains genetic material.
Mitochondria are responsible for processing oxygen and converting substances from the foods we eat into energy for essential cell functions.
The mitochondria of the zygote come from the oocyte, that is, from the mother and almost never from the sperm, form of transmission is called maternal inheritance
Which mitochondrial gene is mutated.
The extent of replicative segregation of the mutant mitochondrial genome during the early stages of embryonic development.
The abundance of the mutant mitochondrial gene in a particular tissue.
The threshold level of mutant mitochondrial DNA required in a tissue before an abnormality is evident clinically
Mitochondrial disease affects tissues most highly dependent on ATP production
*Nerves
*Muscles
Endocrine
Kidney
Low energy-requiring tissues are rarely directly affected, but may be secondarily
Lung
Connective tissue
Symptoms can be intermittent
Increased energy demand (illness, exercise)
Decreased energy supply (fasting)
Common feature
myoclonus epilepsy, deafness, blindness, anemia, diabetes, seizures and loss of cerebral blood supply (stroke).
Myoclonic epilepsy and ragged-red fiber disease (MERRF)
MERRF is a member of a group of disorders called mitochondrial encephalomyopathies that feature mitochondrial defects with altered brain and muscle functions.
The term “ragged red fibers” refers to large clumps of abnormal mitochondria that accumulate mostly in muscle cells and are stained red by a dye that is specific for complex II of the electron transport chain.
rare, maternally inherited, heteroplasmic, (point mutation in tRNA lysine gene)
Mutation is MTTK*MERRF8344G.
MT means mitochondrial gene is mutated
T means transfer RNA gene
K means the single-letter amino acid designation for lysine
MERRF means the clinical features
8344G means the mutant nucleotide is guanine (G) at nucleotide position 8344
If 90% of the mitochondria in nerve and muscle cells carry the MTTK*MERRF8344G mutation, then the defining symptoms of MERRF are present.
Maternally inherited mitochondrial disease
The MTTL1*MELAS3243G mutation accounts for more than 80% of the cases of MELAS.
This base substitution is in one of the two mitochondrial transfer RNALeu genes.
the A3243G mutation occurs in thetRNALeu(UUR) gene
When this mutation is present in ≥90% of the mitochondrial DNA of muscle tissue, there is an increased likelihood of recurrent strokes, dementia, epilepsy, and ataxia.
When heteroplasmy for the A3243G mutation
is ~40% to 50%, chronic progressive external ophthalmoplegia (CPEO), myopathy, and deafness are likely to occur.
Other MELAS mutations occur at sites 3252, 3271, and 3291 within the tRNALeu(UUR) gene and in the mitochondrial tRNAVal (MTTV) and COX III (MTCO3) genes.
Reduced activities in Complexes I and IV are established
Motor neuron disease (MND) refers to conditions characterized by degeneration of upper and lower motor neurons. Amyotrophic lateral sclerosis (ALS) is the most common form of MND and involves both upper and lower motor neurons. ALS is clinically defined based on involvement of motor neurons and includes features such as muscle weakness, atrophy, fasciculations, and stiffness. The pathology of ALS involves degeneration and death of motor neurons in the brain, brainstem, and spinal cord leading to muscle denervation and atrophy. While the cause of ALS is largely unknown, factors such as oxidative stress, protein aggregation, mitochondrial dysfunction, and glutamate excitotoxicity are hypothesized to contribute to motor neuron de
Als Paper & Prion Protein Gene Expressionjosephmdphysics
ALS is a degenerative neurological disease that causes motor neuron cell death leading to paralysis and death from respiratory failure. Free radicals, excess glutamate, calcium release, and genetic mutations contribute to motor neuron cell death. The disease progresses through corticomotor neuron death followed by spinal motor neuron denervation atrophy. Epidemiological studies show organophosphate pesticides and heavy metal exposures increase ALS risk by causing oxidative stress and gene imbalances that further damage cells. Electrophysiology shows abnormal cortical excitability occurs in sporadic ALS patients but not all genetic mutation cases, and excitability worsens with disease progression.
1. The document discusses the genetics of several cognitive disorders in elderly individuals, including Alzheimer's disease, frontotemporal lobar degeneration, Lewy body disease, vascular dementia, and Huntington's disease.
2. For Alzheimer's disease, mutations in the APP, PSEN1, and PSEN2 genes are associated with early-onset familial Alzheimer's, while the APOE ε4 allele is a major genetic risk factor for late-onset Alzheimer's.
3. For frontotemporal lobar degeneration, mutations in the PGRN and MAPT genes are most common, while other genes like C9ORF72 and VCP have also been linked. Genetic causes
This presentation aims at giving a vivid knowledge about Nucleoli, a sub organelle of Nucleus, its role in protein formation. control, localization ad how specifically it is involved in Single Nucleotide polymorphism. The slide also discusses about the involvement of SNPs in Alzheimer’s Disease.
Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that primarily affects the nerve cells (neurons) responsible for controlling voluntary muscle movement (those muscles we choose to move). Voluntary muscles produce movements like chewing, walking, and talking.
Neurobiology of Alzheimer’s disease
Role of Acetyl choline
Amyloid-beta-mediated neurodegeneration
Amyloid beta accumulation
Amyloid cascade hypothesis
Microtubule-associated protein tau
Oxidative stress
ROS-mediated neuronal damage
Strategic Approaches to Age-Related Metabolic Insufficiency and Transition in...InsideScientific
In this webinar, Dr. Dennis Turner delves into dementia syndrome, the metabolic changes that occur, and the importance of proper physiological monitoring of animal models.
Brain metabolism transforms with normal aging, and transient, dynamic metabolic insufficiency may underlie critical progression from aging into dementia syndrome and Alzheimer’s disease (AD). Age-related brain metabolism balances vascular-related substrate supply and transport mechanisms into extracellular space to neurons with cellular metabolic needs and utilization. Dynamic metabolic insufficiency can occur when there is intermittent supply-demand mismatch.
Adequacy of neurovascular coupling to provide sufficient cerebral blood flow (CBF) to meet neuronal demand in vivo in a mouse AD model, compared to aged controls were studied. Dr. Turner’s lab analyzed the response to maximal neuronal metabolic demands, spreading depression and anoxia, using imaging, CBF measurements, and oxygen and glucose levels. These in vivo studies require human-similar anesthesia conditions, through monitoring temperature, blood pressure/pulse oximetry, and respiration, to maintain homeostasis. The lab confirmed abnormal neurovascular coupling in a mouse model of AD in response to these metabolic challenges, showing disruption much earlier in dementia than in equivalently aged individuals. Chronic metabolic treatments could influence dementia syndrome progression.
This document summarizes the role of the transcription factor nuclear factor-kappa B (NF-κB) in the major genetic and environmental risk factors for Alzheimer's disease (AD). It discusses how NF-κB interacts with genes implicated in AD risk, such as APP, APOE, and genes involved in immunity. It reviews evidence from neuronal cell lines, invertebrate models like fruit flies, and vertebrate models like mice that genetic and environmental factors associated with aging increase NF-κB activity and are linked to AD pathology. The document suggests NF-κB may be a key regulator integrating genetic and environmental risk factors and could potentially be targeted for disease prevention.
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
Amyotrophic lateral sclerosis & frontotemporal lobar degeneration summary...Masuma Sani
Amyotrophic lateral sclerosis (ALS) causes motor neuron degeneration in the brain and spinal cord, resulting in progressive muscle weakness and paralysis. Frontotemporal lobar degeneration (FTLD) causes degeneration of neurons in the frontal and temporal lobes, leading to changes in behavior, personality, and language abilities. While ALS and FTLD present as distinct disorders, they share some common pathological features and genetic underpinnings. Mutations in genes involved in RNA processing and transport, like TARDBP, FUS, and C9ORF72, have been linked to both ALS and FTLD and may disrupt nucleocytoplasmic transport of RNA and proteins. Understanding the networks and interactions
1) The Dlx5 homeodomain is a transcription factor linked to several human diseases. Mutations in the DLX5 gene have been associated with split hand and foot malformation syndrome 1 (SHFM1).
2) NMR spectroscopy was used to study the interaction between the Dlx5 homeodomain and DNA, identifying a 14 base pair DNA sequence (CGACTAATTAGTCG) that formed a stable complex.
3) The crystal structure of the Dlx5-DNA complex was determined at 1.85 angstrom resolution, revealing that residues associated with SHFM1 are involved in key interactions for DNA recognition and binding.
So, Who Hopes For A Piece Of Protease ?washocelot8
This document summarizes several novel mutations that have been discovered in myeloproliferative neoplasms (MPNs) including JAK2, MPL, TET2, ASXL1, CBL, IDH, and IKZF1. The mutations have different frequencies in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The functional consequences of these mutations include deregulated JAK-STAT signaling, epigenetic changes, and abnormal protein accumulation, but how they contribute to disease initiation and progression is still unclear. The document focuses on describing the mutations and their associations with the various MPN diseases.
This study identified FUS, a gene frequently mutated in ALS, as autoregulating its own expression through alternative splicing of its pre-mRNA. The study found that FUS binds to and represses the splicing of its own exon 7. This causes the production of an exon 7-skipped splice variant that triggers nonsense-mediated decay, reducing FUS protein levels. Expression of ALS-linked FUS mutants compromised this autoregulation by reducing exon 7 repression and nuclear localization of FUS. This suggests deficient FUS autoregulation could exacerbate cytoplasmic accumulation of FUS in ALS through a feed-forward loop mechanism.
Similar to Oakes et al 2017 TBK1 - a new player in ALS linking autophagy and neuroinflammation (20)
2. genetically European ethnicity and analyzed variants
using a number of inheritance models. This study con-
firmed several previously identified ALS genes and iden-
tified TBK1 as a novel ALS gene [6]. Freischmidt et al.
[7] performed exome sequencing and a targeted muta-
tion screen using high resolution melting curve analysis
which identified TBK1 as an ALS gene in a Swedish
population. Subsequently, a study of Australian fALS
patients identified a novel TBK1 mutation in a family of
Chinese origin, the first TBK1 mutation found in an
Asian ALS patient [11]. This study did not find any
TBK1 mutations in patients of European ancestry and
concluded that TBK1 mutations are rare in Australian
fALS patients [11]. More recently, TBK1 mutations have
been found to be a rare cause of ALS in Taiwanese and
Chinese populations [12, 13], as well as in Sardinian
ALS patients [14]. Frontotemporal dementia (FTD) is a
neurodegenerative disorder closely linked to ALS and
many patients present with both conditions. In a study
of ALS and FTD patients in a French population, TBK1
mutations occurred more frequently in patients with
FTD-ALS comorbidity (10.8%) than in those with ALS
alone (0.5%) [15–17]. Several other studies have identi-
fied TBK1 mutations to be a major cause of FTD either
concurrent with or without ALS [12, 14].
These human genetic studies identified nonsense, frame-
shift, missense and deletion mutations in both sporadic
and familial ALS cases (and ALS-FTD/FTD) dispersed
throughout the TBK1 protein sequence (Fig. 1a). Nonsense
and frameshift mutations cause major disruption to TBK1
and may decrease its expression at both the mRNA and
protein level [7, 17], implying that TBK1 haploinsufficiency
contributes to the development of ALS in these cases.
However, the contribution of missense mutations and
single amino acid deletions are more subtle, as they may or
may not confer either loss of function or reduction in func-
tion. These variants are also less likely to cause a decrease
in expression suggesting haploinsufficiency is not to blame
in these cases. Elucidation of the functional effects of these
variants will contribute to our understanding of ALS
pathogenesis as well as TBK1 function as discussed below.
Molecular pathology of ALS
ALS involves the premature loss of upper and lower
motor neurons, with degeneration of these neurons in the
spinal cord, brainstem and motor cortex [3]. This leads to
weakening and atrophy of muscles and eventually paraly-
sis [1, 3]. At the molecular level, numerous factors affect
ALS pathology including RNA and protein aggregates,
mitochondrial dysfunction and neuroinflammation.
Protein and RNA aggregates
The presence of protein and RNA aggregates in the
cytoplasm of motor neurons is the primary hallmark of
ALS. The most common protein inclusion in ALS is
TDP-43 (encoded by TARDBP). TARDBP mutations are
a cause of both fALS and sporadic ALS (sALS); however,
mutations are not a requirement for formation of aggre-
gates, which may be formed from wild-type proteins.
TDP-43 is an RNA-binding protein normally found in
the nucleus where it has roles in gene expression and
RNA processing. However, cytoplasmic aggregates of
TDP-43 are frequently observed in ALS and these are
often ubiquitinated [1].
C9ORF72, which has roles in stress granule formation,
microglial function and autophagy [18–20], contains a
hexanucleotide GGGGCC repeat in its first intron; ex-
pansion of this repeat is the most frequent cause of fALS
[21]. In healthy individuals, the repeat is <30 copies in
length, however, in ALS patients the number of repeats
may be expanded to hundreds of copies. C9ORF72 ex-
panded repeats result in three types of inclusion: intra-
nuclear RNA foci, cytoplasmic C9ORF72 aggregates,
(which may colocalize with p62 and TDP-43), and di-
peptide repeat proteins produced by RAN-translation
of the expanded region [1, 22]. These abnormal protein
aggregates are thought to be the mechanism by which
Fig. 1 a Primary structure of TBK1. TBK1 is 729 amino acids in length
and comprises four main domains: a kinase domain (KD), ubiquitin-like
domain (ULD) and two coiled-coil domains (CCD1 and CCD2). Locations
of TBK1 mutations associated with ALS and ALS-FTD are indicated
by vertical lines: Black – frame shift mutations, orange – nonsense
mutations, green – Missense mutations, blue – in-frame deletions,
purple – splice mutations and yellow - insertion mutations. b
Tertiary structure of TBK1. The region highlighted in red represents the
kinase domain, the turquoise region represents the ubiquitin-like
domain and the yellow region represents coiled-coil domain 1.
Coiled-coil domain 2 is not shown in this model. Diagram produced
in PyMOL using crystal structure data published by Larabi et al.
2013 [40] accessed via protein databank (accession number: 4IWO).
(RCSB Protein Data Bank, 2016)
Oakes et al. Molecular Brain (2017) 10:5 Page 2 of 10
3. C9ORF72 expanded repeats contribute to ALS. C9ORF72
transcription in heterozygous 311005021Rik (C9ORF72
mouse ortholog) knock-in C57BL/6 mice is highest in neu-
rons of the hippocampus, cerebellum, cortex, brainstem
nuclei and striatum, all of which are known to degenerate
in ALS and FTD [23]. This suggests that C9ORF72 repeat
expansion related pathology would be most potent in these
regions, providing some insight into the cell-specificity of
neuronal degeneration in C9ORF72-ALS.
SOD1 was the first ALS gene identified and it is widely
studied due to the availability of the SOD1-G93A mouse
model of ALS [24]. Mutations in SOD1 produce an
unstable protein which is deposited in the cytoplasm;
oligomerisation of unstable SOD1 leads to aggregate
formation [25]. FUS is another RNA binding protein in
which mutations can result in the formation of cytoplas-
mic aggregates. It is a component of stress granules and
may form p62 and TDP-43 positive aggregates [1]. TDP-
43 positive protein inclusions, as well as C9ORF72
repeat expansion pathologies, are also involved in FTD
and ALS-FTD.
The mechanism by which these inclusions contribute
to ALS and FTD pathogenesis is as yet undefined,
though they are thought to impair axonal transport [3].
It is also unclear as to whether the inclusions them-
selves are cytotoxic or if they are secondary to another
primary pathology [1, 22]. It is postulated that impaired
autophagy could be a contributing factor to the accu-
mulation of cytoplasmic aggregates [26]. TBK1 has im-
portant roles in autophagy [27] and it seems likely that
it is by this mechanism that TBK1 mutations contribute
to ALS.
Mitochondrial dysfunction
Mitochondria have important roles in cellular respir-
ation, calcium buffering and apoptosis. Neurons are par-
ticularly sensitive to mitochondrial dysfunction given
their high metabolic rate [28] and the presence of abnor-
mal or dysfunctional mitochondria in neurons is thought
to be a contributing factor in ALS. The presence of mu-
tant SOD1 in the cytoplasm of motor neurons plays a
major role in mitochondrial dysfunction resulting in
impaired ATP production, impaired calcium buffering
and early apoptosis of neuronal cells [29–31]. Calcium is
critical to the correct functioning of motor neurons as it
has major roles in metabolism, development, and syn-
aptic transmission. Early apoptosis is brought about by
the interaction of SOD1 and mitochondrial apoptotic
machinery, this process directly contributes to motor
neuron degeneration [32].
Transport of substances along the length of motor
neurons is crucial for normal function and disruption of
axonal transport of mitochondria has been observed
in both ALS patients and animal models [33, 34].
Mitochondria are transported along motor neurons to
areas of greatest metabolic need and calcium regula-
tion; disruption of this process leads to reduced ATP
availability and dysregulation of calcium levels result-
ing in neuron damage. Disruption of axonal transport
also potentiates the accumulation of protein and RNA
aggregates discussed above, this leads to further im-
pairment of axonal transport resulting in motor neuron
degeneration [3]. Damage to motor neurons as a result of
protein aggregate accumulation and mitochondrial
dysfunction leads to secondary non-neuronal cell
causes of motor neuron degeneration such as neuro-
inflammation [1].
Neuroinflammation
Glial cells are the principle innate immune cell of the
CNS and pathology associated with these cells is referred
to as neuroinflammation [35], a hallmark of ALS. Glial
cells primarily express the Toll-like receptors TLR3 and
TLR4 [36]; ligand binding results in activation and mi-
gration of glial cells towards sites of damage where they
dispose of damaged cells through phagocytosis. A by-
product of this process is the production of neurotoxic
molecules such as pro-inflammatory cytokines and
reactive oxygen species. These molecules may cause
further neuronal damage leading to further glial cell acti-
vation resulting in a positive feedback loop of neuroin-
flammation [35]. TBK1 is involved in the innate immune
response by regulating the production of IFNα and
IFNβ. Ligand binding of TLR3 or TLR4 results in re-
cruitment of adaptor proteins TRIF and TRAM. TRIF
interacts with TRAF3 resulting in activation of TBK1/
IKKi hetero- or homo-dimers which in turn phosphoryl-
ate IRF-3 and IRF-7 allowing the formation of homodi-
mers. IRF-3/IRF-7 homodimers are transported to the
nucleus where they act as transcription factors for
IFNα and IFNβ [37]. TBK1 is also involved in TLR in-
dependent antiviral signaling involving intracellular
RIG-I-like receptors (RLRs). Ligand binding of RLRs
leads to TBK1 activation through a complex pathway
involving the outer mitochondrial membrane (OMM)
protein MAVS and the adaptor protein STING [38].
T cells have been observed in spinal cord lesions of
ALS patients and are thought to play a role in the regu-
lation of neuroinflammation. CD4+ cells stabilize micro-
glial activation, decrease pro-inflammatory cytokines and
increase growth factor IGF-1 suggesting that T cells play
a protective role in ALS [35]. Migration of T cells from
the lymph nodes is impaired in TBK1 knockout mice
[39], potentially resulting in decreased T cell number in
the CNS. This may increase the damage caused by neu-
roinflammation by removing the protective regulation by
T cells.
Oakes et al. Molecular Brain (2017) 10:5 Page 3 of 10
4. TBK1 structure and function
Protein structure and regulation
TBK1 contains four domains: a serine/threonine kinase
domain (KD) (residues 1–307) located at its N-terminal, a
ubiquitin-like domain (ULD) (residues 308–383) and two
coiled-coil domains, coiled-coil domain 1 (CCD1) (residues
407–657) and coiled-coil domain 2 (CCD2) (residues
658–713) http://www.uniprot.org/uniprot/Q9UHD2 [40].
(Fig. 1). CCD1 is also referred to as a scaffold dimerization
domain (SDD) [7, 40, 41]. TBK1 may form a homodimer
or a heterodimer with IKKi; formation of a homodimer is
primarily mediated by interactions between the two CCD1
domains however, the KDs and ULDs also interact with
the adjacent molecule. The interacting residues forming
the dimer are conserved and are required for activation, a
process that requires TBK1 dimerisation [42].
The KD is comprised of two lobes termed N-terminal
and C-terminal lobes, with the active site situated
between these two lobes. The KD also contains an acti-
vation loop (Leu164-Gly199) which includes Ser172,
phosphorylation of which brings about TBK1 activation.
In the inactive form, the activation loop protrudes away
from the KD towards the C-lobe of the KD of the other
TBK1 protein comprising the dimer. A conserved resi-
due, Glu55, is also displaced from the active site. It is
speculated that TBK1 dimers are able to autophosphory-
late through the interaction of adjacent KDs and activa-
tion loops. Phosphorylation of Ser172 results in a
conformational change of the activation loop. The acti-
vation loop retracts towards and interacts with its own
KD allowing substrate binding. The conserved Glu55 resi-
due is also rotated into a position where it can form a salt
bridge with Lys38. Other than this, conformational
changes as a result of phosphorylation are limited [40, 43].
Poly-ubiquitination of Lys30 and Lys401 is a require-
ment for activation of TBK1 and a multistep mechanism
of TBK1 activation beginning with poly-ubiquitination
of Lys30 and Lys401 followed by phosphorylation of
Ser172 has been suggested [42]. This results in a con-
formational change of the active site to allow substrate
binding. Along with the KD, the ULD is also important
for the kinase activity of TBK1; deletion of the ULD re-
sults in a loss of kinase activity [44]. Sequence alignment
of the TBK1 ULD with similar human ULDs and ULDs
of TBK1 from other species has identified many struc-
turally important conserved residues. Three residues,
Leu316, Ile353, and Val382, are suspected to be involved
in protein-protein interactions [41]. These residues form
a hydrophobic patch homologous to the hydrophobic
patch of ubiquitin (Leu316, Ile44, and Val70) [41]. Ubi-
quitin interacts with its binding partners via this hydro-
phobic patch, indicating that TBK1 may also interact
with proteins via this structure. The hydrophobic patch
is also thought to be involved in interactions between
the TBK1 ULD and CCD1. Comparison of the surface
charge of various regions of ULDs of IKK-family ki-
nases reveals that it differs between family members
and these differences may determine substrate specifi-
city [41]. Mutations around the hydrophobic patch have
been demonstrated to prevent activation of downstream
molecules of TBK1 [41].
TBK1 is regulated by adaptor proteins that control its
localization, activation and participation in different sig-
naling pathways [45, 46]. TBK1 possesses the ability to
robustly autophosphorylate, and therefore requires strict
regulation. This, alongside the fact that TBK1 plays roles
in many pathways including induction of interferons and
autophagy, means that the subcellular localization of
TBK1 may contribute to its regulation as well as its sig-
naling specificity [47]. NAP1, TANK, and Sintbad are
adaptor proteins that bind to the CCD2 domain of
TBK1. These adaptor proteins bind in a mutually exclu-
sive manner and the differing subcellular localization of
these adaptors may determine the pathway in which
TBK1 will participate [46]. This is supported by findings
that TBK1 activated in autophagy does not result in acti-
vation of its downstream targets in the innate immunity
signaling, this suggests that there is limited crosstalk
between the different TBK1 pathways [48]. NAP1 and
Sintbad are localized diffusely throughout the cytoplasm
whereas TANK is punctate in the perinuclear region, this
has led to suggestions that binding of TANK results in
the induction of IFNα and IFNβ whereas binding of
NAP1 or Sintbad is more important for autophagy [49].
A network of 30 proteins interacting with one or more
of these adaptor proteins and/or TBK1/IKKi has been
established [46]. This all suggests that adaptor binding
to TBK1 plays a key role in its activation and function
within the cell.
TBK1 mutations
We collated 92 TBK1 mutations identified in patients
with ALS, ALS-FTD or FTD from eight human genetics
studies (Table 1, Additional file 1: Table S1 and Fig. 1).
88 of these mutations were identified in ALS patients
(ALS and ALS with FTD) of which 27 are potential loss
of function variants (nonsense, splice site and frameshift
Table 1 Breakdown of TBK1 mutations by disease type and
protein domains
Domain
Disease Kinase domain Ubiquitin-like
domain
CCD1 CCD2
ALS 32 (84%) 11 (100%) 29 (71%) 2 (25%)
ALS-FTD 2 (5%) 0 (0%) 9 (22%) 4 (50%)
FTD 4 (11%) 0 (0%) 3 (7%) 2 (25%)
Total no. cases 38 11 41 8
Oakes et al. Molecular Brain (2017) 10:5 Page 4 of 10
5. mutations) and 16 are in-frame insertions/deletions.
Freischmidt et al. identified 8 heterozygous loss of func-
tion variants, of which 7 resulted in the loss of expres-
sion of TBK1 and therefore were reported as causative
via haploinsufficiency [7]. The loss of function variant
that was expressed (p.690-713del) contained a deletion in
the CCD2 domain that prevented binding of OPTN, indi-
cating that this may be sufficient to cause ALS/FTD [7].
The majority of ALS-associated TBK1 variants (45)
identified to date are missense mutations (Fig. 2,
Additional file 1: Table S1) of unknown pathogenicity.
The functional relevance of these variants is less obvious
than nonsense or frameshift mutations, which lead to loss
of expression of TBK1. Missense mutations may be patho-
genic if the site is crucial to the function or stability of the
protein. Mutations in the KD may affect phosphoryl-
ation of substrates whereas mutations within the ULD
may affect recruitment to ubiquitinated proteins and
organelles. CCD1 is important for TBK1 dimerisation
and mutations here could affect this process, which is
required for TBK1 activation [42]. CCD2 domain muta-
tions could interfere with adaptor binding and TBK1
activation [46].
Mutations in the KD and CCD1 account for a greater
proportion of disease cases than mutations in the ULD
or CCD2 (Table 1, Additional file 1: Table S1) but when
domain size is taken into account, mutations are evenly
distributed across all domains of TBK1 (Fig. 1). KD,
ULD and CCD1 mutations occur more frequently in
ALS cases whereas CCD2 mutations seem more likely to
result in ALS-FTD or FTD. However, larger numbers of
patients with TBK1 mutations are needed to confirm
any potential domain-specific associations. Using tools
to predict the functional effects of mutations, the largest
proportion of missence mutations that are probably
damaging, occur in the kinase domain (Additional file 1:
Table S1). However, biochemical analysis of variants
located in each domain of TBK1 revealed functional
deficits in TBK1 in four out of five cases, indicating that
many missence mutations have the potential to be
pathogenic [7]. Determining which TBK1 missence mu-
tations cause selective loss of function of TBK1 could
shed light on the functions of TBK1 most relevant to
disease.
Autophagy and the role of TBK1
Autophagy
Autophagy is a process by which ubiquitinated proteins
and damaged organelles are degraded and recycled.
Abnormal protein aggregates are a hallmark of ALS
pathology, in addition to this, mutations in several genes
involved autophagy have been associated with ALS includ-
ing SQSTM1 (encodes p62), SOD1, OPTN, VCP, UBQLN2
and most recently TBK1. This suggests that disruption of
autophagy is important in ALS pathophysiology [1, 50].
Autophagy begins with the formation of an immature
membrane structure called a phagophore in response to
signaling initiated by phosphorylation of the ULK1-
ATG13-FIP200 complex [51]. This is normally inhibited
by mTORC1, however, the action of mTORC1 can, in
turn, be inhibited by AMPK [26]. The activated ULK1-
ATG13-FIP200 complex triggers movement of another
complex containing beclin1 and PI3K CIII towards a
phagophore. This complex mediates elongation of the
phagophore membrane and envelopment of proteins or
organelles marked for degradation, resulting in the for-
mation of a double-membrane bound autophagosome.
The process of autophagosome formation is also medi-
ated by two interlinked control systems, the Atg5-Atg12
conjugation system [52] and the microtubule-associated
protein 1A/1B LC3 conjugation system [53]. The Atg5-
Atg12 conjugation system results in the formation of a
complex of Atg5-Atg12-Atg16. This complex allows
conjugation of LC3 with phosphatidyl-ethanolamine to
produce LC3-II [50], which then binds to the surface of
a phagophore where it has roles in elongation and
cargo recruitment [26]. The autophagosome is trans-
ported along a microtubule to a lysosome-rich area.
The autophagosome fuses with a lysosome forming an
autophagolysosome, the contents of which are digested
[50] (Fig. 3).
Autophagy adaptors enhance disposal of cargo, such
as ubiquitinated proteins and damaged mitochondria, by
linking them with autophagosome-associated proteins
such as LC3-II [50]. Many of the ALS-associated inclu-
sions described previously contain p62 and ubiquitin.
Ubiquitination of proteins marks them for degradation;
autophagy adaptors recruit ubiquitinated proteins to the
phagophore by linking ubiquitin and LC3-II. p62 and
Fig. 2 Frequency of different types of ALS and FTD-associated TBK1
mutations. Summary of data compiled in Additional file 1: Table S1
Oakes et al. Molecular Brain (2017) 10:5 Page 5 of 10
6. OPTN are autophagy adaptors and mutations in these
proteins result in impaired autophagy and are recog-
nized causes of ALS [54, 55]. Importantly, p62, OPTN,
and another autophagy adaptor NDP52 are all regulated
by phosphorylation by TBK1 [48].
The presence of abnormal protein inclusions in the
brain is a common feature of ALS and neurons can re-
spond to this accumulation by upregulating autophagy
[56]; if autophagy is disrupted, this may contribute to
neurodegeneration and the pathology of ALS. This
hypothesis is supported by the loss of autophagy in the
CNS of Atg7−/−
and Atg5−/−
mice (two genes essential
for autophagy), resulting in neurodegenerative disease
[57, 58]. Loss of neurons, increased apoptosis and in-
creased protein aggregation were evident when autophagy
was decreased [57, 58]. The fact that several ALS genes
are involved in autophagy and the knowledge that forma-
tion of protein aggregates contribute to ALS pathogenesis,
suggests that disruption of autophagy is of importance to
the development of ALS. The various roles of TBK1 in
autophagy, especially adaptor phosphorylation, suggests
that this may also be an important process in the contri-
bution of TBK1 mutations to ALS.
TBK1 also plays a role in innate immunity, chiefly the in-
duction of type-I interferons, alongside its aforementioned
role in autophagy. These roles seem to be largely distinct
and only limited crosstalk is evident. Interferons, induced
by TBK1, lead to the transcription of interferon-inducible
genes, amongst the targets of type-I interferons is ISG15,
which has been linked to autophagy [59, 60]. ISG15 inter-
acts with p62 and HDAC6, a protein with roles in cargo
aggregation and autophagolysosome formation [61]. Over-
expression of ISG15 results in enhanced aggregate forma-
tion and autophagy [60]. ISG15 can also suppress
autophagy by binding beclin1 and PI3K CIII [59]; proteins
important in phagophore elongation [26]. Loss of TBK1
decreases ISG15 and therefore removes its suppression of
autophagy. In addition to this, enhanced aggregate forma-
tion was only observed with overexpression of ISG15
[60]. These factors suggest that ISG15 related mecha-
nisms are probably not important in the contribution
of mutant TBK1 to ALS; however, this highlights an
interesting link between two TBK1 pathways.
Autophagy, TBK1 and ALS pathogenesis
TBK1 plays key roles in autophagy, including the phos-
phorylation of a number of autophagy adaptors including
p62, OPTN and NDP52 [48], enhancing their ability to
link LC3-II and ubiquitinated cargo (Fig. 3) [26]. Phos-
phorylation of OPTN and p62 involves interaction with
Fig. 3 Autophagolysosome formation and maturation. Autophagy involves the formation of an isolation membrane. This membrane undergoes
elongation, forming a phagophore and a portion of the cytoplasm is separated to form an autophagosome. This involves the ULK1-ATG13-FIP200,
Beclin1-PI3K CIII and Atg5-Atg12-Atg16 complexes The autophagosome fuses with a lysosome to form an autophagolysosome, allowing digestive
enzymes to degrade any material in the vesicle. TBK1 binds and phosphorylates autophagy receptors OPTN and p62; they bind to ubiquitin residues
on target cargo and to LC3-II. This enhances the ability of the receptors to bind ubiquitinated residues on target cargo and LC3-II. This all allows
ubiquitinated cargo to be recruited to the phagophore for degradation; the receptors act as adaptors that link cargo to autophagic machinery
Oakes et al. Molecular Brain (2017) 10:5 Page 6 of 10
7. the CCD2 domain of TBK1 [15]. Several TBK1 mutations
identified in ALS patients cause protein truncation
resulting in loss of CCD2 [7], decreasing the ability of
TBK1 to phosphorylate these molecules. In addition to
this, some TBK1 mutations result in decreased mRNA
and protein levels [7, 17], which may decrease activation
of autophagy adaptors, resulting in decreased autophagy
and accumulation of protein aggregates in motor neurons.
TBK1 has also been implicated in autophagosome
maturation. In TBK1 knockdown cells, autophagosome
formation was not disrupted whereas maturation of
autophagosomes into autophagolysosomes was inhibited
[27]. Rab8b is an upstream regulator of TBK1 and they
both colocalize with LC3 on autophagosomes; this inter-
action is proposed as a mechanism by which TBK1 is in-
volved in autophagosome maturation [27]. Maturation
of autophagosomes involves transport to a lysosome-rich
area via microtubules, this is dependent on the action of
the motor protein dynein [62]. TBK1 regulates micro-
tubule dynamics in mitosis and the cytoplasmic levels of
dynein [63]. Disruption of microtubule transport due to
loss of TBK1 could contribute to ALS by the impaired
maturation of autophagosomes into autophagolysosomes.
Several studies have attempted to characterize neuro-
pathological features associated with TBK1-ALS and
FTD, though overall the number of individuals examined
is still low. An ALS patient carrying a TBK1 mutation
has been found with both TDP-43 positive and p62 posi-
tive inclusions in motor neurons as well as TDP-43
inclusions in the cortex [64]. An FTD patient from the
same study was found to have TDP-43 inclusions in vari-
ous brain regions as well as cytoplasmic p62 and
ubiquitin-positive inclusions in glial cells [64]. Another
study found TDP-43 positive inclusions in three out of
five TBK1-FTD patients [17] and another found both
TDP-43 and p62 positive inclusions in various brain re-
gions of a TBK1-FTD/ALS patient [7]. These findings,
particularly of p62 and ubiquitin-positive inclusions,
provide further indications that TBK1 mutations may
contribute to ALS through impaired autophagy.
Mitophagy, TBK1 and ALS pathogenesis
Recent studies have identified important roles for TBK1
and other ALS genes in autophagy of mitochondria,
specifically known as mitophagy [48, 65]. In the PINK1-
Parkin pathway, PINK1 is able to detect damaged mito-
chondria by crossing the outer mitochondrial membrane
(OMM). If the mitochondrion is healthy, PINK1 passes
through the OMM and is degraded on the inner mitochon-
drial membrane (IMM). However, if the mitochondrion is
damaged PINK1 is retained on the OMM where it accumu-
lates and phosphorylates ubiquitin chains on several OMM
proteins resulting in binding of autophagy adaptors [48].
PINK1 concurrently recruits and phosphorylates Parkin,
resulting in its activation. Parkin is an E3 ubiquitin ligase
that constructs ubiquitin chains on OMM proteins, which
are then phosphorylated by PINK1, allowing further
adaptor binding [65]. TBK1 can then be activated by a
mechanism dependent on Parkin, OPTN, NDP52 and
OPTN-ubiquitin binding ability [48]. Activated TBK1 can
phosphorylate NDP52, OPTN, and p62, greatly enhancing
their ability to link ubiquitin and LC3-II [65]. Phosphoryl-
ation of OPTN enhances its ubiquitin binding ability and
its role in TBK1 activation resulting in a positive feedback
mechanism of TBK1 and OPTN activation [48, 65]. NDP52
and OPTN are able to bring about mitophagy by linking
ubiquitinated OMM proteins and LC3 proteins on phago-
phores resulting in engulfment and digestion of mitochon-
dria [26].
The role of p62 in mitophagy is controversial; several
studies have reported that p62 is not essential for mito-
phagy but plays a role in the aggregation of ubiquiti-
nated mitochondria [48, 65]. On the other hand, it has
also been reported that activation of p62 is required for
efficient mitophagy [66]. TBK1 is required for efficient
recruitment of autophagy adaptors and efficient mito-
phagy, and TBK1 is essential for mitophagy via OPTN
[48, 65]. Loss of TBK1 function would result in impaired
mitophagy and accumulation of defective mitochondria,
which may contribute to ALS by disrupting axonal
transport that occurs in ALS [67].
Recent studies have added further weight to the argu-
ment that TBK1 mutations contribute to ALS through
impaired autophagy/mitophagy. The E696K missense
mutation identified in ALS patients [7, 17] occurs in the
TBK1 CCD2 domain that interacts with adaptor proteins
such as OPTN. This mutation disrupts two hydrogen
bonds with H52 and K55 on the N-terminal domain of
OPTN, which in turn disrupts the OPTN-TBK1 complex.
Co-localization of TBK1 with OPTN is also reduced fol-
lowing the E696K mutation, with co-immunoprecipitation
studies showing that the mutation almost completely
abolishes the interaction between the two proteins [68].
Whilst wild-type TBK1 localizes to damaged mitochon-
dria, the E696K mutant exhibited severely reduced coloca-
lization with damaged mitochondria [69]. This suggests
that this process is dependent on OPTN, due to the loss
of TBK1-OPTN binding in the E696K mutant. This po-
tentially provides evidence that defective mitophagy is a
pathogenic mechanism in TBK1-ALS.
Tissue specificity and importance of age in TBK1-ALS
Autophagy can play one of two roles in the cell; to de-
grade proteins, regardless of cell stress, via continuous
operation at low levels (basal autophagy) or to supply
amino acids for cell survival during poor environmental
conditions (adaptive autophagy) [70]. Basal autophagy in
neuronal cells is crucial to their integrity. Most cells can
Oakes et al. Molecular Brain (2017) 10:5 Page 7 of 10
8. dilute damaging agents through cell division, whereas
the post-mitotic nature of neuronal cells means that they
require autophagy to remove toxic proteins [71]. This
implies a high level of basal autophagy in these cells, an
idea supported by the high autophagic efficiency sug-
gested by the rarity of autophagic vacuoles in healthy
neurons [72]. Given the high level of autophagic activity
required for neuronal maintenance, it is not surprising
that these tissues are particularly susceptible to damage
through disruption of autophagy.
TBK1 is normally expressed diffusely in the cytoplasm
at moderate levels in all tissues but is expressed at a
much higher level in neuronal cells of the cerebral cor-
tex, hippocampus and lateral ventricle [73]. Moderate
TBK1 levels are also seen in the glial cells of the cerebral
cortex, Purkinje cells and granular layer cells in the
cerebellum [73]. ALS is characterized by loss of spinal,
cerebellar, hippocampal, brain stem and cortical motor
neurons [23], as well as a loss of pyramidal neurons in
the primary motor cortex. The fact that TBK1 expres-
sion is high in neurons of the CNS which are then lost
during ALS, may suggest that loss of function TBK1 mu-
tations may have a greater effect in these cells. TBK1 is
also highly expressed in various other tissues, including
the lungs, endocrine tissues and skin [73]. This begs the
question as to why the major effects of ALS are only ob-
served in nervous tissue. This may be explained by a
threshold for development of pathology that may not be
reached in these other tissues.
Advanced age appears to be an important factor in the
development of ALS and this may be due to a number
of factors. A reduction in the number of motor neurons
is a normal part of aging and this can contribute to
sarcopenia, the age-related loss of muscle mass [74]. In
addition to this, the uptake of heavy metals into spinal
cord neurons is also increased with advancing age [74];
exposure to heavy metals is a risk factor of ALS due to
increased glutamate excitotoxicity [3]. Recovery of motor
function is decreased in an aged ALS mouse model
when compared to their younger counterparts [75].
Finally, the rate of autophagy declines with age leading
to a reduction of the ability of cells to remove protein
aggregates [76], or indeed damaged mitochondria which
may be particularly detrimental to neurons. These factors
may contribute to the tissue specificity of TBK1 involve-
ment in ALS, regardless of its widespread expression. It is
unlikely that defects in TBK1 related pathways suddenly
appear at some point in the course of advancing age but
instead the threshold required to cause disease is lowered
to the point where these defects become pathological. In
other words, age-related factors such as sarcopenia, heavy
metal accumulation, and impaired neuronal recovery may
facilitate the progression of ALS due to defective TBK1
signaling.
Future outlook
TBK1 is involved in a variety of ALS-relevant pathways
such as autophagy and neuroinflammation. TBK1 func-
tion, pathological findings in ALS and known pathogenic
mechanisms of ALS point towards autophagy as the
major contribution of TBK1 mutations to ALS. Defective
autophagy may lead to the accumulation of protein ag-
gregates, autophagosomes and damaged mitochondria in
motor neurons. This may all result in impaired axonal
transport of molecules and organelles, such as mito-
chondria, which are crucial for neuron function and sur-
vival. Given the varied and crucial roles of TBK1 in
autophagy and mitophagy, it seems that these mecha-
nisms may be paramount in the contribution of TBK1 to
ALS pathogenesis. Impaired mitochondrial function and
transport may result in neuronal damage by the mecha-
nisms discussed above. Neuronal damage may trigger in-
nate responses by cells surrounding neurons leading to
neuroinflammation, another important mechanism in
ALS pathogenesis. Further dissection of TBK1 signaling
pathways in neurons will help further our understanding
of the contribution of TBK1 mutations to ALS. Given a
large number of downstream targets of TBK1 that have
been identified, relatively few have been investigated
thoroughly. Studies comparing the pathological findings
in different ALS genotypes may also aid our understand-
ing of how different genes/pathways contribute to ALS.
Additional file
Additional file 1: Dataset of TBK1 mutations identified in ALS/FTD
patients compiled from the literature. (PDF 478 kb)
Abbreviations
ALS: Amyotrophic lateral sclerosis; AMPK: AMP-activated protein kinase;
Atg(5,12,13,16): Autophagy-related (5,12,13,16); ATP: Adenosine triphosphate;
C9ORF72: Chromosome 9 open reading frame 72; CCD(1,2): Coiled-coil
domain; CNS: Central nervous system; fALS: Familial amyotrophic lateral
sclerosis; FIP200: Focal adhesion kinase family interacting protein of 200 kD;
FTD: Frontotemporal dementia; FUS: Fused in sarcoma; HDAC6: Histone
deacetylase 6; IFN(α,β): Interferon; IFN: Interferon; IGF-1: Insulin-like growth
factor 1; IKK(α,β,ε/i): IκB kinase; IMM: Inner mitochondrial membrane;
IRF(3,7): Interferon regulatory factor; ISG15: Interferon-stimulated gene 15;
IκB: Inhibitor of kappa B; KD: Kinase domain; LC3: Microtubule-associated
protein 1A/1B-light chain 3; MAVS: Mitochondrial antiviral signalling protein;
mTORC1: Mammalian transport of rapamycin complex 1; NAK: NFκB
activating kinase; NAP1: Nucleosome assembly protein 1; NDP52: Nuclear dot
protein 52 kDa; NFκB: Nuclear factor kappa-light-chain-enhancer of activated
B cells; OMM: Outer mitochondrial membrane; OPTN: Optineurin; PI3K
CIII: Phosphoinositide 3-kinase class III; PINK1: Phosphatase and tensin homolog
(PTEN)-induced putative kinase 1.; RAN-translation: Repeat-associated non-ATG
translation; RLR: Rig-I-like receptor; sALS: Sporadic amyotrophic lateral sclerosis;
SDD: Scaffold dimerisation domain; SOD1: Superoxide dismutase 1;
SQSTM1: Sequestosome-1; STING: Stimulator of interferon genes; T2K: TRAF2
kinase; TANK: TRAF family member-associated NF-kappa-B activator; TARDBP/
TDP-43: Transactive response DNA binding protein 43; TBK1: TANK-binding
kinase 1; TLR(3,4): Toll-like receptor; TRAF(2,3): TNF receptor-associated
factor; TRAM: Translocating chain-associating membrane protein; TRIF:
TIR-domain-containing adapter-inducing interferon-β; UBQLN2: Ubiquilin-2;
ULD: Ubiquitin-like domain; ULK1: Unc-51 Like Autophagy Activating
Kinase 1; VCP: Valosin-containing protein
Oakes et al. Molecular Brain (2017) 10:5 Page 8 of 10
9. Acknowledgements
Not applicable.
Funding
This work was supported by a research grant (R/144823-11-1) from the Royal
Society.
Availability of data and materials
Not applicable.
Authors’ contributions
JAO, MCD, and MOC wrote the manuscript. All authors read and approved
the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
As this study did not involve any animal or human participants, human data
or human tissue, ethical committee approval is not required.
Author details
1
School of Medicine, University of Sheffield, Sheffield, UK. 2
Department of
Biomedical Science, University of Sheffield, Firth Court, Western Bank,
Sheffield S10 2TN, UK.
Received: 21 June 2016 Accepted: 24 January 2017
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