2014 11-25 presentación lactrims matute - lima (peru)
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This document summarizes key points about mitochondria and mitochondrial dysfunction in multiple sclerosis (MS). It discusses how mitochondria provide energy to axons and oligodendrocytes through oxidative phosphorylation. Excitotoxicity can damage mitochondria in oligodendrocytes. Mitochondrial defects are seen in neurons, axons, and oligodendrocytes in MS. Demyelination impairs energy supply from oligodendrocytes to axons. Glutamate and calcium overload can induce mitochondrial damage and cell death. Mitochondrial dysfunction leads to energy failure and vulnerability of demyelinated axons to degeneration in MS lesions.
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This document summarizes a study examining the relationship between impaired brain insulin signaling, amyloid-beta oligomers (AbOs), tau, and cell cycle reentry (CCR) in Alzheimer's disease (AD) pathogenesis. The study finds that AbOs activate the protein kinase mTORC1, which then phosphorylates tau and induces CCR in neurons. CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. As AbOs also reduce neuronal insulin signaling, decreased insulin signaling allows the toxic effects of AbOs to cause CCR and neuronal death, contributing to AD progression. The findings help explain how impaired brain insulin signaling may promote AD by unleashing the cell cycle reentry effects of Ab
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El lunes y martes 20 y 21 de noviembre coordinamos un simposio internacional en la Fundación Ramón Areces, sobre los defectos del transporte de aminoácidos.
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The document discusses several key concepts in molecular genetics including:
1. The central dogma which states that DNA is transcribed into RNA and then translated into protein.
2. Complementary base pairing rules where A pairs with T and C pairs with G in DNA, and A pairs with U in RNA.
3. Translation is the process where mRNA is used to produce proteins using codons of three nucleotides that code for amino acids.
4. Mutations can occur in DNA and affect proteins, including frameshift, point, silent, missense, and nonsense mutations.
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This document summarizes a medical student's research on the differential effects of the protein kinase C-eta (PKCη) on apoptosis versus senescence. The student conducted experiments using cell culture, transfection, and Western blot analysis to determine that depletion of PKCη induces senescence and upregulates the protein p27, leading to resistance to chemotherapy, while depletion of p27 can restore apoptosis. The research contributes to understanding PKCη's controversial roles in tumor promotion and suppression and could help develop more targeted chemotherapy treatments.
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Vitamin C plays an important role in the nervous system. It reaches high concentrations in neurons due to the SVCT2 transporter. In the brain, vitamin C acts as an antioxidant, helps form myelin sheaths, and protects against toxins. It is also involved in neurotransmitter synthesis and synaptic function. Vitamin C enters the brain through the choroid plexus into the cerebrospinal fluid and then into brain cells, maintaining high concentrations despite low blood levels. It has various roles in brain function and antioxidant defenses in the central nervous system.
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Rv1075c is a conserved hypothetical protein in Mycobacterium tuberculosis that shares similarities to bacterial lipases and esterases. A study identified that Rv1075c has esterase activity, preferring short-chain fatty acids like acetate. Mutation of Rv1075c led to reduced bacterial growth in macrophages and mice. The study exposed M. tuberculosis strains expressing wild-type or mutated Rv1075c to stress conditions and infected macrophages and mice to determine Rv1075c expression and effects on infection. Results demonstrated Rv1075c induction during low pH stress and its role in M. tuberculosis survival and virulence through fatty acid hydrolysis.
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The document provides an overview of the complement system including:
1) It describes the three pathways of complement activation - the classical, lectin, and alternative pathways. It explains the proteins involved in each pathway and their functions.
2) Regulatory mechanisms of complement activation are discussed including factors and receptors that inhibit inappropriate complement activation on host cells.
3) The biological functions of complement activation are summarized including opsonization, initiation of inflammation, and direct lysis of pathogens.
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This document summarizes a study examining the relationship between impaired brain insulin signaling, amyloid-beta oligomers (AbOs), tau, and cell cycle reentry (CCR) in Alzheimer's disease (AD) pathogenesis. The study finds that AbOs activate the protein kinase mTORC1, which then phosphorylates tau and induces CCR in neurons. CCR can be prevented by insulin-stimulated activation of lysosomal mTORC1. As AbOs also reduce neuronal insulin signaling, decreased insulin signaling allows the toxic effects of AbOs to cause CCR and neuronal death, contributing to AD progression. The findings help explain how impaired brain insulin signaling may promote AD by unleashing the cell cycle reentry effects of Ab
Florence Molinari INMED-INSERM U901. Marseille.
El lunes y martes 20 y 21 de noviembre coordinamos un simposio internacional en la Fundación Ramón Areces, sobre los defectos del transporte de aminoácidos.
3 8 Main Pp
The document discusses several key concepts in molecular genetics including:
1. The central dogma which states that DNA is transcribed into RNA and then translated into protein.
2. Complementary base pairing rules where A pairs with T and C pairs with G in DNA, and A pairs with U in RNA.
3. Translation is the process where mRNA is used to produce proteins using codons of three nucleotides that code for amino acids.
4. Mutations can occur in DNA and affect proteins, including frameshift, point, silent, missense, and nonsense mutations.
When proteins misbehave (part 3)
Prion proteins are naturally occurring proteins found in brain cells that play roles in neuronal signaling and protection. When prion proteins misfold, they can influence other prion proteins to misfold as well, leading to prion diseases. Misfolded prion proteins are resistant to the cell's quality control system and cause neurodegeneration. A recent study found that a single misfolded prion protein molecule can be highly toxic, challenging theories that protein aggregates are always required for toxicity. Misfolded proteins may also play a role in diabetes by damaging insulin-producing pancreatic cells and disrupting protein quality control in the endoplasmic reticulum.
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This document summarizes a medical student's research on the differential effects of the protein kinase C-eta (PKCη) on apoptosis versus senescence. The student conducted experiments using cell culture, transfection, and Western blot analysis to determine that depletion of PKCη induces senescence and upregulates the protein p27, leading to resistance to chemotherapy, while depletion of p27 can restore apoptosis. The research contributes to understanding PKCη's controversial roles in tumor promotion and suppression and could help develop more targeted chemotherapy treatments.
Vitamin c.role in cns.
Vitamin C plays an important role in the nervous system. It reaches high concentrations in neurons due to the SVCT2 transporter. In the brain, vitamin C acts as an antioxidant, helps form myelin sheaths, and protects against toxins. It is also involved in neurotransmitter synthesis and synaptic function. Vitamin C enters the brain through the choroid plexus into the cerebrospinal fluid and then into brain cells, maintaining high concentrations despite low blood levels. It has various roles in brain function and antioxidant defenses in the central nervous system.
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Rv1075c is a conserved hypothetical protein in Mycobacterium tuberculosis that shares similarities to bacterial lipases and esterases. A study identified that Rv1075c has esterase activity, preferring short-chain fatty acids like acetate. Mutation of Rv1075c led to reduced bacterial growth in macrophages and mice. The study exposed M. tuberculosis strains expressing wild-type or mutated Rv1075c to stress conditions and infected macrophages and mice to determine Rv1075c expression and effects on infection. Results demonstrated Rv1075c induction during low pH stress and its role in M. tuberculosis survival and virulence through fatty acid hydrolysis.
Disorders of the complement system
The document provides an overview of the complement system including:
1) It describes the three pathways of complement activation - the classical, lectin, and alternative pathways. It explains the proteins involved in each pathway and their functions.
2) Regulatory mechanisms of complement activation are discussed including factors and receptors that inhibit inappropriate complement activation on host cells.
3) The biological functions of complement activation are summarized including opsonization, initiation of inflammation, and direct lysis of pathogens.
4) Complement-related disorders are briefly mentioned including those associated with deficiencies in early classical pathway components.
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This document describes research into developing an RNA aptamer antagonist of NMDA receptors for potential therapeutic applications. Key points:
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This study investigated signal transduction pathways activated by stimulation of I1-imidazoline receptors in PC12 cells. The study found that stimulation of these receptors with moxonidine:
1) Increased the activity of PKC beta II and redistributed the atypical PKC zeta isoform into cell membranes. It did not affect the novel PKC theta isoform.
2) Increased the proportion of active, phosphorylated forms of ERK-1 and ERK-2, as well as increasing JNK enzymatic activity.
3) The effects of moxonidine on ERK activation were blocked by an I1 receptor antagonist and a PC-PLC inhibitor, suggesting PC-PLC mediates I
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CLE peptides are small plant peptide hormones that mediate cell-to-cell communication and play important roles in plant growth, stem cell maintenance, and environmental responses. CLE peptides signal through receptors like CLV1 and TDR to regulate processes like stem cell homeostasis and vascular development. Studies showed that swapping amino acids in CLE peptides can change their receptor binding specificity and functions, demonstrating the importance of individual amino acids for CLE peptide activity and signaling. Further understanding of CLE peptide signaling could provide tools to modify plant development for crop improvement.
A Double Point Mutation In The Selectivity Filter Site
1) A double point mutation in the selectivity filter of the KCNQ1 potassium channel was found in three family members with long QT syndrome.
2) This mutation resulted in an isoleucine to lysine change at amino acid 313. The patients displayed prolonged QT intervals and episodes of syncope.
3) Modeling showed the mutation is located in the channel pore. Cells transfected with the mutant plasmid lacked current, and it had a dominant negative effect on current.
Cell signaling transduction mechanisms
1. Cell signaling involves the synthesis, release, and transport of signaling molecules like neurotransmitters and hormones that bind to receptors on target cells.
2. This triggers signal transduction pathways inside the cell that cause changes in cell behavior.
3. The cell then responds accordingly through actions like releasing other molecules or changing its activity level.
signal transduction
Signal transduction pathways allow plants to respond to environmental stimuli. Receptors on the plasma membrane or inside the cell detect stimuli and activate secondary messengers like calcium or G-proteins. These messengers activate effector molecules like protein kinases that modulate gene expression and trigger responses like tolerance to abiotic stresses. Manipulating these pathways could help protect plants from stresses under climate change.
Lesson 16 mutations
Mutations are caused by mistakes during DNA replication or cell division that produce a new DNA sequence. There are three main types of mutations: gene mutations which create new gene alleles, chromosome structure mutations from errors during crossing over, and numerical mutations resulting from alterations in chromosome number such as trisomies and monosomies. Mutations can have consequences like genetic disorders but also contribute to genetic variability in populations.
Li, Lisanti, Puszkin - Purification and molecular characterization of NP185
This study further characterized the neuronal protein NP185/AP3 through several experiments:
1) Microsequence analysis of purified native NP185 from bovine brain yielded five peptide fragments that matched sequences of mouse F1-20 and rat AP180 proteins.
2) Recombinant NP185/AP3 purified using genetic methods facilitated the reconstruction of clathrin cages in an established assay.
3) Deletion mutagenesis mapped the epitopes of two monoclonal antibodies that recognize bovine NP185 to a 60 amino acid region of recombinant murine NP185/AP3.
4) Recombinant NP185/AP3 was phosphorylated by purified casein kinase II in vitro.
Synthesis of Proteins or the Formation of the Conga Line
The document summarizes the process of protein synthesis from DNA to proteins. It describes how nucleic acids like DNA and RNA carry genetic information through their sequence of nucleotides. DNA is transcribed into mRNA in the nucleus, then mRNA is translated by ribosomes in the cytoplasm to produce proteins based on the mRNA's codon sequences. Transfer RNA molecules bring amino acids to the ribosome according to each codon, and the amino acids are joined through peptide bonds to form a polypeptide chain.
Second Messenger: cAMP Pathway
This document summarizes the cyclic AMP (cAMP) signaling pathway. It describes how extracellular signaling molecules called first messengers bind to G protein-coupled receptors, activating G proteins that stimulate the enzyme adenylyl cyclase to produce the second messenger cAMP. cAMP then activates the protein kinase A pathway and triggers cellular responses. Negative feedback mechanisms like phosphorylation and recruitment of arrestins terminate the signal by desensitizing the receptor. The cAMP pathway is an important intracellular signaling system that relays signals from surface receptors to drive changes in cell metabolism, proliferation, and other functions.
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Expression and localization of proteins in tissue determines anatomy and physiology, and thus provides a clue to pathology. However, it is strenuous to identify the expression and localization of multiple targets using conventional immunostaining technique, especially when there is no specific antibody, nor explicit assumption, for target proteins. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry is a proteomic technique to simultaneously map multiple targets in a frozen tissue section. Using this technique, we analyzed protein expression in heart, and in testis as a reference sample, in 129/sv mice. Spatial distribution of at least 57 individual proteins was simultaneously identified at 100 um resolution. Among them, cardiac alpha actin, cardiac troponin T, tropomyosin alpha-1 chain, titin, myosin light chain 1 (MYL1), myosin light chain 3 (MYL3), myosin-6 were exclusively expressed in the heart. MYL1 and MYL3, the altered expression of which is associated with heart failure, were localized in the atrium and in the ventricle, respectively, as expected. Interestingly, protein expression profile of cysteine-rich protein 2 and myomesin-1 is exactly as predicted from mRNA expression, namely more in the heart and less in the testis. Expression level of housekeeping genes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta actin, was similar between the heart and the testis. These results suggest that MALDI imaging may provide a new platform for analysis of pathology and subsequent application to diagnosis of heart diseases.
Ablooglu et al 2001 Nat Str Biol
This document summarizes the design and testing of a bisubstrate inhibitor for the insulin receptor tyrosine kinase (IRK). Researchers designed a compound that links ATPγS to a peptide substrate analog via a two-carbon spacer, setting the distance between the nucleophilic atom and phosphoryl group to mimic a dissociative transition state as suggested by previous studies of IRK's mechanism. Testing found this compound to be a potent and selective competitive inhibitor of IRK, with a Ki of 370 nM, making it the most potent inhibitor reported for this important signaling enzyme. A crystal structure confirmed the inhibitor bound as designed and validated the mechanism-inspired approach.
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This study examined the role of IKKα kinase activity in regulating NF-κB target gene expression using gene expression profiling. Rescuing wild-type IKKα in IKKα knockout mouse embryonic fibroblasts globally restored expression of canonical NF-κB targets. Surprisingly, rescuing a kinase-dead IKKα mutant also rescued expression of approximately 28% of these genes, both independently of and dependently on TNFα stimulation. Thus, IKKα regulates NF-κB target gene expression through both kinase-dependent and independent mechanisms in both stimulus-dependent and independent manners. Five distinct classes of IKKα/NF-κB-dependent genes were identified.
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This document discusses amyloid-beta (Aβ) and tau in Alzheimer's disease (AD) pathogenesis. It states that Aβ accumulation triggers AD, and that Aβ oligomers interact with tau signaling pathways, leading to tau hyperphosphorylation and neurofibrillary tangles. Hyperphosphorylated tau then disrupts axonal transport. The document outlines various therapeutic targets for AD, including reducing Aβ accumulation, inhibiting tau hyperphosphorylation, and supporting acetylcholine and glutamate signaling.
Mitochondrion in neurodegeneration and neuroprotection
The mitochondrion plays a key role in neurodegeneration through a balance of pro-survival and pro-apoptotic proteins on its outer membrane. BAX damages the membrane by forming pores, while Bcl-2 protects it by patching pores. When damage exceeds repair, caspases are activated, leading to apoptosis, autophagy, or necrosis. Many neurodegenerative diseases involve unwanted apoptosis due to elevated BAX and caspase levels. Some psychotropic drugs like lithium, valproate, and certain antidepressants and antipsychotics exert neuroprotective effects by increasing Bcl-2 levels.
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Phosphorylation of serine 526 in the activation loop of MEKK3 is required for its kinase activity and ability to activate downstream signaling pathways. Mutation of serine 526 to alanine abolished MEKK3 activity, while mutation to aspartic or glutamic acid created constitutively active mutants. Serine 526 is autophosphorylated and its phosphorylation is regulated by protein phosphatase 2A and its association with 14-3-3 proteins, which prevents dephosphorylation. Phosphorylation of endogenous MEKK3 on serine 526 occurs in response to osmotic stress.
Garam Lee NMDA
This document describes research into developing an RNA aptamer antagonist of NMDA receptors for potential therapeutic applications. Key points:
- Researchers used SELEX (Systematic Evolution of Ligands by EXponential enrichment) to isolate an RNA aptamer (clone C26) that selectively binds to GluN2A-containing NMDA receptors with high affinity (Kd = 120 ± 15 nM), while having little effect on closely related AMPA and kainate receptors.
- Electrophysiological characterization found this aptamer (C26-50) selectively inhibits GluN2A-containing NMDA receptors without affecting other receptor subtypes. It acts as a non-competitive antagonist with an IC50 of 1
2014 BDSRA Micsenyi LINCL and JNCL
This document summarizes research on lysosomal membrane permeability (LMP) and its implications for neurodegenerative diseases like neuronal ceroid lipofuscinoses (NCLs). The researchers found evidence that LMP occurs in mouse models of two forms of NCL, CLN2 and CLN3, resulting in the formation of protein aggregates. Normally, LMP triggers a response to sequester damaged lysosomes, but this "lysophagy" response is impaired in NCL models. As a result, aggregates containing lysosomal contents accumulate and may contribute to neurodegeneration. The researchers are testing the drug arimoclomol, which could prevent LMP, in hopes of reducing neurodegeneration in CL
Protein kinases
Protein kinases are enzymes that phosphorylate other proteins and cause functional changes in target proteins. There are over 500 types of protein kinases in genomes that can modify about 30% of proteins. Protein kinase A, C, and G are three important protein kinases that are regulated by different mechanisms and have various functions in different cell types. Protein kinases play critical roles in many cellular processes and their dysregulation can lead to diseases like cancer.
The I1 Imidazoline Receptor In Pc12 Pheochromocytoma Cells
This study investigated signal transduction pathways activated by stimulation of I1-imidazoline receptors in PC12 cells. The study found that stimulation of these receptors with moxonidine:
1) Increased the activity of PKC beta II and redistributed the atypical PKC zeta isoform into cell membranes. It did not affect the novel PKC theta isoform.
2) Increased the proportion of active, phosphorylated forms of ERK-1 and ERK-2, as well as increasing JNK enzymatic activity.
3) The effects of moxonidine on ERK activation were blocked by an I1 receptor antagonist and a PC-PLC inhibitor, suggesting PC-PLC mediates I
Missense mutation and non-sense mutation (molecular biology)
Nonsense mutation: A nucleotide substitution that creates a new stop codon is called a nonsense mutation.
Missense mutation: Nucleotide substitutions in protein-coding regions that do result in changed amino acids are called missense mutations or nonsynonymous mutations.
Cle peptides the power of moving around
CLE peptides are small plant peptide hormones that mediate cell-to-cell communication and play important roles in plant growth, stem cell maintenance, and environmental responses. CLE peptides signal through receptors like CLV1 and TDR to regulate processes like stem cell homeostasis and vascular development. Studies showed that swapping amino acids in CLE peptides can change their receptor binding specificity and functions, demonstrating the importance of individual amino acids for CLE peptide activity and signaling. Further understanding of CLE peptide signaling could provide tools to modify plant development for crop improvement.
A Double Point Mutation In The Selectivity Filter Site
1) A double point mutation in the selectivity filter of the KCNQ1 potassium channel was found in three family members with long QT syndrome.
2) This mutation resulted in an isoleucine to lysine change at amino acid 313. The patients displayed prolonged QT intervals and episodes of syncope.
3) Modeling showed the mutation is located in the channel pore. Cells transfected with the mutant plasmid lacked current, and it had a dominant negative effect on current.
Cell signaling transduction mechanisms
1. Cell signaling involves the synthesis, release, and transport of signaling molecules like neurotransmitters and hormones that bind to receptors on target cells.
2. This triggers signal transduction pathways inside the cell that cause changes in cell behavior.
3. The cell then responds accordingly through actions like releasing other molecules or changing its activity level.
signal transduction
Signal transduction pathways allow plants to respond to environmental stimuli. Receptors on the plasma membrane or inside the cell detect stimuli and activate secondary messengers like calcium or G-proteins. These messengers activate effector molecules like protein kinases that modulate gene expression and trigger responses like tolerance to abiotic stresses. Manipulating these pathways could help protect plants from stresses under climate change.
Lesson 16 mutations
Mutations are caused by mistakes during DNA replication or cell division that produce a new DNA sequence. There are three main types of mutations: gene mutations which create new gene alleles, chromosome structure mutations from errors during crossing over, and numerical mutations resulting from alterations in chromosome number such as trisomies and monosomies. Mutations can have consequences like genetic disorders but also contribute to genetic variability in populations.
Li, Lisanti, Puszkin - Purification and molecular characterization of NP185
This study further characterized the neuronal protein NP185/AP3 through several experiments:
1) Microsequence analysis of purified native NP185 from bovine brain yielded five peptide fragments that matched sequences of mouse F1-20 and rat AP180 proteins.
2) Recombinant NP185/AP3 purified using genetic methods facilitated the reconstruction of clathrin cages in an established assay.
3) Deletion mutagenesis mapped the epitopes of two monoclonal antibodies that recognize bovine NP185 to a 60 amino acid region of recombinant murine NP185/AP3.
4) Recombinant NP185/AP3 was phosphorylated by purified casein kinase II in vitro.
Synthesis of Proteins or the Formation of the Conga Line
The document summarizes the process of protein synthesis from DNA to proteins. It describes how nucleic acids like DNA and RNA carry genetic information through their sequence of nucleotides. DNA is transcribed into mRNA in the nucleus, then mRNA is translated by ribosomes in the cytoplasm to produce proteins based on the mRNA's codon sequences. Transfer RNA molecules bring amino acids to the ribosome according to each codon, and the amino acids are joined through peptide bonds to form a polypeptide chain.
Second Messenger: cAMP Pathway
This document summarizes the cyclic AMP (cAMP) signaling pathway. It describes how extracellular signaling molecules called first messengers bind to G protein-coupled receptors, activating G proteins that stimulate the enzyme adenylyl cyclase to produce the second messenger cAMP. cAMP then activates the protein kinase A pathway and triggers cellular responses. Negative feedback mechanisms like phosphorylation and recruitment of arrestins terminate the signal by desensitizing the receptor. The cAMP pathway is an important intracellular signaling system that relays signals from surface receptors to drive changes in cell metabolism, proliferation, and other functions.
Simultaneous mapping of multiple proteins in heart using matrix-assisted lase...
Expression and localization of proteins in tissue determines anatomy and physiology, and thus provides a clue to pathology. However, it is strenuous to identify the expression and localization of multiple targets using conventional immunostaining technique, especially when there is no specific antibody, nor explicit assumption, for target proteins. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry is a proteomic technique to simultaneously map multiple targets in a frozen tissue section. Using this technique, we analyzed protein expression in heart, and in testis as a reference sample, in 129/sv mice. Spatial distribution of at least 57 individual proteins was simultaneously identified at 100 um resolution. Among them, cardiac alpha actin, cardiac troponin T, tropomyosin alpha-1 chain, titin, myosin light chain 1 (MYL1), myosin light chain 3 (MYL3), myosin-6 were exclusively expressed in the heart. MYL1 and MYL3, the altered expression of which is associated with heart failure, were localized in the atrium and in the ventricle, respectively, as expected. Interestingly, protein expression profile of cysteine-rich protein 2 and myomesin-1 is exactly as predicted from mRNA expression, namely more in the heart and less in the testis. Expression level of housekeeping genes, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta actin, was similar between the heart and the testis. These results suggest that MALDI imaging may provide a new platform for analysis of pathology and subsequent application to diagnosis of heart diseases.
Ablooglu et al 2001 Nat Str Biol
This document summarizes the design and testing of a bisubstrate inhibitor for the insulin receptor tyrosine kinase (IRK). Researchers designed a compound that links ATPγS to a peptide substrate analog via a two-carbon spacer, setting the distance between the nucleophilic atom and phosphoryl group to mimic a dissociative transition state as suggested by previous studies of IRK's mechanism. Testing found this compound to be a potent and selective competitive inhibitor of IRK, with a Ki of 370 nM, making it the most potent inhibitor reported for this important signaling enzyme. A crystal structure confirmed the inhibitor bound as designed and validated the mechanism-inspired approach.
nihms2969
This study examined the role of IKKα kinase activity in regulating NF-κB target gene expression using gene expression profiling. Rescuing wild-type IKKα in IKKα knockout mouse embryonic fibroblasts globally restored expression of canonical NF-κB targets. Surprisingly, rescuing a kinase-dead IKKα mutant also rescued expression of approximately 28% of these genes, both independently of and dependently on TNFα stimulation. Thus, IKKα regulates NF-κB target gene expression through both kinase-dependent and independent mechanisms in both stimulus-dependent and independent manners. Five distinct classes of IKKα/NF-κB-dependent genes were identified.
Nrn ad posters- nature
This document discusses amyloid-beta (Aβ) and tau in Alzheimer's disease (AD) pathogenesis. It states that Aβ accumulation triggers AD, and that Aβ oligomers interact with tau signaling pathways, leading to tau hyperphosphorylation and neurofibrillary tangles. Hyperphosphorylated tau then disrupts axonal transport. The document outlines various therapeutic targets for AD, including reducing Aβ accumulation, inhibiting tau hyperphosphorylation, and supporting acetylcholine and glutamate signaling.
Mitochondrion in neurodegeneration and neuroprotection
The mitochondrion plays a key role in neurodegeneration through a balance of pro-survival and pro-apoptotic proteins on its outer membrane. BAX damages the membrane by forming pores, while Bcl-2 protects it by patching pores. When damage exceeds repair, caspases are activated, leading to apoptosis, autophagy, or necrosis. Many neurodegenerative diseases involve unwanted apoptosis due to elevated BAX and caspase levels. Some psychotropic drugs like lithium, valproate, and certain antidepressants and antipsychotics exert neuroprotective effects by increasing Bcl-2 levels.
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Li, Lisanti, Puszkin - Purification and molecular characterization of NP185
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Common molecular mechanisms and pathways leading to neurodegeneration, such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease or Multiple Sclerosis, are presented in this slideshow. Learn more about research and therapeutic strategies as well as how these discoveries and tools can be used to facilitate your neurodegeneration research.
Oxidative stress
This document defines oxidative stress as an imbalance between reactive oxygen species and antioxidants in cells. It describes how reactive oxygen species are naturally produced through processes like oxidative phosphorylation but can also come from external sources like pollution. The document lists some common reactive oxygen and nitrogen species and endogenous and exogenous antioxidants. It explains that damage from oxidative stress can lead to diseases like atherosclerosis, cancer, and cardiovascular diseases.
Oxidative stress and disease
Oxidative stress occurs when there is an imbalance between reactive oxygen species and antioxidants in the body, leading to oxidative damage of DNA, proteins, and lipids. It has been implicated in aging and many diseases such as atherosclerosis, rheumatoid arthritis, and cancers. Antioxidants like vitamins A, C, E, and enzymes including superoxide dismutase, catalase, and the glutathione system help combat oxidative stress. The glutathione system consists of glutathione, NADPH, and related enzymes that are essential for its proper function. Glucose-6-phosphate dehydrogenase deficiency can impair the glutathione system.
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Use RT2 Profiler PCR Arrays to profile gene expression of key
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may determine cell fate decision under oxidative stress.
Free Radicals
Reactive oxygen and nitrogen species (ROS/RNS) are highly reactive molecules that can damage cells. They include radicals like superoxide and hydroxyl, as well as non-radical species like hydrogen peroxide. ROS/RNS are produced through normal cellular processes but also from external sources like radiation and pollutants. They can cause oxidative damage to lipids, proteins, and DNA if not neutralized by antioxidant defenses. This oxidative stress has been linked to many diseases due to disruption of redox signaling and control in the cell.
13. free radicals and antioxidants
Free radicals are unstable molecules that can damage cells. They are formed through normal metabolic processes but also due to environmental toxins and radiation. The body has antioxidant defenses against free radicals but an excess can lead to oxidative stress and disease. Endogenous free radicals include reactive oxygen species like superoxide, hydrogen peroxide, and hydroxyl radicals produced during metabolism. Exogenous sources include tobacco smoke, drugs, radiation, and air pollution. Free radical damage accumulates with age and is linked to many age-related diseases.
Free radicals
Free radicals are atoms, molecules, or ions with unpaired electrons that make them highly reactive. They are formed through processes like homolysis and oxidation-reduction reactions. Free radical stability is determined by factors like conjugation, hybridization, and hyperconjugation which disperse and stabilize the unpaired electron. Common examples of stable radicals include molecular oxygen and organic radicals within conjugated systems.
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Mitochondrial disorders overview
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Mitochondrial disorders
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
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Disclaimer: No one is perfect, so please mind that there might be mistakes and typos.
dtubbenhauer@gmail.com
Corrected slides: dtubbenhauer.com/talks.html
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and around Westerlund 1. Sources were detected by combining various existing methods, and photon extraction and source validation
were carried out using the ACIS-Extract software.
Results. The EWOCS X-ray catalog comprises 5963 validated sources out of the 9420 initially provided to ACIS-Extract, reaching a
photon flux threshold of approximately 2 × 10−8 photons cm−2
s
−1
. The X-ray sources exhibit a highly concentrated spatial distribution,
with 1075 sources located within the central 1 arcmin. We have successfully detected X-ray emissions from 126 out of the 166 known
massive stars of the cluster, and we have collected over 71 000 photons from the magnetar CXO J164710.20-455217.
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2014 11-25 presentación lactrims matute - lima (peru)
- 1. www.excemed.org IMPROVING THE PATIENT’S LIFE THROUGH MEDICAL EDUCATION 2014 Pre LACTRIMS conference on progressive MS 26 November 2014 - Lima, Perù
- 2. 2 Private funding Novartis, Biogen, Merck KGaA Public funding MINECO, CIBERNED, Gobierno Vasco Faculty disclosure Universidad del País Vasco / Euskal Herriko Unibertsitatea Carlos Matute e-mail: carlos.matute@ehu.es
- 3. Mitochondrial alterations in Multiple Sclerosis Outline: • An introduction to mitochondria, the cell powerhouse • Oligodendrocytes supply lactate to myelinated axons • Excitotoxicity in oligodendrocytes damages mitochondria • Mitochondrial defects in MS: neurons, axons and oligodendrocytes
- 4. Oxidative phosphorylation Intermediate metabolism Ca2+ homeostasis Mitochondria: a multi-functional organelle Apoptosis
- 5. Mitochondrial function relevance in white matter • In white matter: axons & oligodendrocytes rely on mitochondrial function to support neurotransmission • In oligodendrocytes, mitochondrial function is essential for viability and myelin synthesis (Acetyl-CoA) • In astrocytes, ATP is critical for the control of glutamate metabolism • Axons → High energy demand (primarily ATP) • N-acetylaspartate (NAA) – Neuronal integrity marker – Synthesized in neuronal mitochondria – Converted to acetate by oligodendrocytes for myelin synthesis
- 6. Three main mitochondrial homeostatic disruptions 1. Energy failure: [ATP]↓↓ 2. Oxidative Stress: ROS > antioxidant systems 3. Ca2+ overload Central features of all neurodegenerative disorders Physiologycal Pathological
- 7. Saab et al (2013) Curr Op Neurobiol Myelin supplies energy substrates to axons
- 8. submitted Oligodendroglial NMDA receptors regulate axonal energy metabolism Demyelination impairs energy supply to axons
- 9. Models of Disease Pathogenesis in Multiple Sclerosis Hauser and Oksenberg 2006 Neuron ATP Demyelination, oligodendrocyte death, axonal damage, neuronal loss, atrophy
- 10. Glutamate and ATP in excess is toxic to oligodendrocytes and myelin MBP TUNEL CNPase CNPase Matute 1998 PNAS USA
- 11. Glutamate levels are elevated in multiple sclerosis Magnetic resonance spectroscopy at 3 T astrogliosis Srinivasan et al 2005 Brain
- 12. Glutamate and ATP toxicity in oligodendrocytes PI – dead cells KAINATE or ATPCONTROL FDA – live cells Matute et al 1997 PNAS USA
- 13. CELL DEATH ROS AIF Nucleus DNA fragmentation PARP-1 Procaspase 8 t-Bid Caspase 3,6,7 Caspase 8 FADD Bid AMPA-RVGCC Na+ Ca2+ m Bcl-2 Cyt c Apaf-1 Caspase 9 CdP P P P Bad Bad 14-3- 3 Bcl-xl KAINATE-R [Ca2+]i Ca2+ VGCC Calpain Bax Sánchez-Gómez et al. J Neurosci 2003 Sánchez-Gómez et al., J Neurosci, 2011 Mitochondria at the crossroads of excitotoxicity in oligodendrocytes
- 14. Butt, Fern, Matute (2014 ) Glia Glutamate and ATP signaling are central to MS pathophysiology Neuroinflammation favors excitotoxic-mediated mitochondrial damage
- 15. • Altered glutamate homeostasis induces mitochondrial damage • Presence of high NO: oxidative stress • Myelin loss-induced trophic imbalance • Expression of mitochondrial respiratory chain complex I, II and III is reduced in MS active lesions and motor cortex • mtDNA defects associated with MS • Abnormal intra-axonal mitochondria prior to axon disruption • Low N-acetyl aspartate levels in acute and chronic lesions and in normal appearing WM Mitochondrial dysfunctions in MS
- 16. Franklin y Ffrench-Constant 2008 Nat Rev Neurosci Persistent demyelination leads to axonal damage Atrophy: loss of axons and neurons
- 17. Axons transiently adapt to demyelination Early response to demyelination Waxman 2006, Nat Rev Neurosci
- 18. Demyelinated axons are more vulnerable to energy failure and therefore to mitochondrial dysfunction → Axonal degeneration in MS Mitochondrial dysfunction → Energy failure → Na+ / K + ATPase↓ → Depolarization → sustained Na+ influx → Reverse activity of the Na+ / Ca2+ exchanger → Ca2+ overload → Axonal damage Non-remyelinated axons ultimately degenerate Late response to demyelination Waxman 2006, Nat Rev Neurosci
- 19. Mechanisms of axonal damage during inflammation and demyelination Waxman 2006, Nat Rev Neurosci
- 20. Ca2+ overload in mitochondria initiates axonal failure in MS Abou-Sleiman et al. 2006 Nat Rev Neurosci
- 21. Ca2+ overload and mPTP opening in MS • Cyclophilin D is a key regulator of the permeability transition pore (mPTP) opening. • CyPD KO neurons were resistant to oxidative stress and NO, and tolerated higher levels of mitochondrial Ca2+ • CyPD KO-EAE mice partially recovered and preserved axonal integrity. Forte et al. 2007, PNAS
- 22. Conclusions 1. White matter is highly dependent on mitochondrial ATP to propagate electric signals, maintain ionic gradients and facilitate axonal transport 2. Inflammation, oxidative stress and Ca2+ homeostasis disruption lead to mitochondrial dysfunction and energy failure in MS 3. Demyelinated axons in MS lesions are more vulnerable to energy failure and mitochondrial dysfunction 4. ROS and Ca2+ damage axons by inducing mitochondrial mPTP opening.
- 23. María Domercq Alberto Pérez Samartín Fernando Pérez Cerdá Fabio Cavaliere Elena Alberdi Vicky Sánchez Olatz Pampliega Olatz Oyanguren Estibaliz Etxeberria Nuria Vázquez Estibaliz Gonzalez Juan Carlos Chara Hospital de Basurto, Bilbao Alfredo Rodríguez-Antigüedad MPI, Göttingen Frank Kirchhoff AECOM, New York Eliana Scemes Universidad del País Vasco, Leioa, Spain Acknowledgments