This document discusses mitochondrial complex 1 involvement in Parkinson's disease. It provides background on complex 1, its structure and role in electron transport chain. Complex 1 dysfunction leads to oxidative damage, particularly in nuclear and mitochondrial encoded subunits. This reduces complex 1 catalytic activity and ATP production. Mutations in genes like Tfam and environmental toxins such as MPP+ and rotenone also inhibit complex 1, increasing reactive oxygen species and contributing to Parkinson's pathogenesis. Therapies aim to prevent complex 1 inhibition or reduce oxidative stress.
This document provides an overview of cell membranes and transport systems. It begins by defining the cell membrane and outlining its key functions, including maintaining cell integrity, selective permeability, and transport. It then describes the fluid mosaic model of the cell membrane's structure, which is composed of a phospholipid bilayer with embedded and peripheral proteins. Various types of membrane proteins and their functions are also discussed. The document focuses on different mechanisms of transport across the membrane, including simple diffusion, facilitated diffusion, active transport (primary and secondary), ion channels, and transporter proteins. Specific transport proteins like glucose transporters and ion pumps/channels are highlighted as examples.
Pharmacotherapy of Alzheimer's disease
Introduction
History
Risk factors
Pathophysiology
Symptoms
Diagnosis
Non pharmacological treatment
Drugs used in treatment of Alzheimer`s
Recent advances
Screening methods
Summary
References
This document provides an overview of Alzheimer's disease including its causes, symptoms, stages, diagnosis, and treatment approaches. It discusses how Alzheimer's is characterized by plaques and tangles in the brain made up of beta-amyloid and tau proteins. Current treatment aims to improve cognitive function and behaviors through cholinesterase inhibitors and memantine, though none can stop or reverse the disease. Non-pharmacological interventions like education, communication, and stimulation therapies may provide additional support.
This document discusses several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. It provides details on the causes, symptoms, pathophysiology, and treatment of Alzheimer's disease. The key points are: Alzheimer's disease causes the progressive loss of neurons and death of brain cells, resulting in memory loss and cognitive decline. The exact cause is unknown but abnormal protein clumps called amyloid plaques and tau tangles are found in the brains of Alzheimer's patients. The disease attacks brain cells and destroys connections between neurons. Current treatments cannot stop the progression but may temporarily slow symptoms.
This presentation provide knowledge about Gene Expression & its regulation in brief.
i hope it gives some information about gene expression in your academic time.
In this presentation mentioned - Lac Operon and its expressor.
The cytochrome P450 system (CYP) is a large family of heme-containing enzymes that catalyze the oxidation of organic substances, including drugs and toxins. CYP enzymes are primarily located in the liver and intestine and are responsible for metabolizing approximately 75% of clinically used drugs. Variability in CYP gene expression between individuals can significantly impact drug metabolism and response. Drug interactions occur when one drug inhibits or induces the activity of a CYP enzyme, altering the metabolism of other drugs that are CYP substrates and potentially causing toxic effects. Careful consideration of a patient's complete medication regimen is important to avoid dangerous drug-drug interactions mediated by the CYP system.
Genetic variation and its role in health pharmacologyDeepak Kumar
Genetic variation exists at different scales, from single nucleotide polymorphisms within individuals of a species to larger structural differences between species. Genetic variation arises through mutations, recombination, gene flow, genetic drift, and the interaction of these processes over time. The effective population size of a species influences how genetic variation is shaped by these evolutionary forces.
This document provides an overview of cell membranes and transport systems. It begins by defining the cell membrane and outlining its key functions, including maintaining cell integrity, selective permeability, and transport. It then describes the fluid mosaic model of the cell membrane's structure, which is composed of a phospholipid bilayer with embedded and peripheral proteins. Various types of membrane proteins and their functions are also discussed. The document focuses on different mechanisms of transport across the membrane, including simple diffusion, facilitated diffusion, active transport (primary and secondary), ion channels, and transporter proteins. Specific transport proteins like glucose transporters and ion pumps/channels are highlighted as examples.
Pharmacotherapy of Alzheimer's disease
Introduction
History
Risk factors
Pathophysiology
Symptoms
Diagnosis
Non pharmacological treatment
Drugs used in treatment of Alzheimer`s
Recent advances
Screening methods
Summary
References
This document provides an overview of Alzheimer's disease including its causes, symptoms, stages, diagnosis, and treatment approaches. It discusses how Alzheimer's is characterized by plaques and tangles in the brain made up of beta-amyloid and tau proteins. Current treatment aims to improve cognitive function and behaviors through cholinesterase inhibitors and memantine, though none can stop or reverse the disease. Non-pharmacological interventions like education, communication, and stimulation therapies may provide additional support.
This document discusses several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. It provides details on the causes, symptoms, pathophysiology, and treatment of Alzheimer's disease. The key points are: Alzheimer's disease causes the progressive loss of neurons and death of brain cells, resulting in memory loss and cognitive decline. The exact cause is unknown but abnormal protein clumps called amyloid plaques and tau tangles are found in the brains of Alzheimer's patients. The disease attacks brain cells and destroys connections between neurons. Current treatments cannot stop the progression but may temporarily slow symptoms.
This presentation provide knowledge about Gene Expression & its regulation in brief.
i hope it gives some information about gene expression in your academic time.
In this presentation mentioned - Lac Operon and its expressor.
The cytochrome P450 system (CYP) is a large family of heme-containing enzymes that catalyze the oxidation of organic substances, including drugs and toxins. CYP enzymes are primarily located in the liver and intestine and are responsible for metabolizing approximately 75% of clinically used drugs. Variability in CYP gene expression between individuals can significantly impact drug metabolism and response. Drug interactions occur when one drug inhibits or induces the activity of a CYP enzyme, altering the metabolism of other drugs that are CYP substrates and potentially causing toxic effects. Careful consideration of a patient's complete medication regimen is important to avoid dangerous drug-drug interactions mediated by the CYP system.
Genetic variation and its role in health pharmacologyDeepak Kumar
Genetic variation exists at different scales, from single nucleotide polymorphisms within individuals of a species to larger structural differences between species. Genetic variation arises through mutations, recombination, gene flow, genetic drift, and the interaction of these processes over time. The effective population size of a species influences how genetic variation is shaped by these evolutionary forces.
G protein coupled receptors and their Signaling MechanismFarazaJaved
G protein-coupled receptors (GPCRs) are a large family of receptors that span cell membranes and activate intracellular signaling pathways in response to extracellular stimuli. They are activated by a wide range of ligands including light, hormones, and neurotransmitters. Upon ligand binding, GPCRs activate heterotrimeric G proteins, which then initiate intracellular signaling cascades. The three main G protein families - Gs, Gi, and Gq - activate or inhibit different downstream effector enzymes to elicit a cellular response. Dysregulation of GPCRs and their associated signaling pathways can lead to various diseases.
An 80-year-old man presented with symptoms of Alzheimer's disease including memory loss, disorientation, difficulty completing tasks, and mood changes. Brain scans and examination of brain tissue confirmed Alzheimer's disease. Alzheimer's is caused by abnormal accumulation of tau and amyloid-beta proteins in the brain, which form plaques and tangles that damage neurons. It is diagnosed based on symptoms, cognitive tests, and brain imaging, and progresses from mild to severe impairment over time. There are medications to temporarily improve symptoms but no cure for the underlying disease process.
Cytochrome P450 enzymes are important for metabolizing xenobiotics in the body. There are many CYP isoforms located in the liver and intestine that catalyze phase I and phase II reactions to make xenobiotics more hydrophilic for excretion. Phase I reactions like oxidation and hydroxylation introduce reactive or polar groups. Phase II conjugates these compounds with glucuronic acid, glutathione, sulfate, or acetyl groups which greatly increases their water solubility and allows them to be secreted from cells and eliminated from the body. Several drug transporters then efflux the conjugated metabolites out of cells and across barriers to complete their removal from the body. Cytochrome P450 enzymes play a vital role in both the de
Cell death, also known as programmed cell death, occurs through various pathways including apoptosis, autophagy, and necrosis. Apoptosis, or programmed cell death, involves two main pathways - the intrinsic pathway which is triggered by cellular stress and the extrinsic pathway which is triggered by death ligands binding to cell surface death receptors. Both pathways activate caspases that break down cellular components leading to cell death. Autophagy is the natural and regulated mechanism by which cells degrade and recycle unnecessary or dysfunctional cellular components through the formation of autophagosomes and lysosomal degradation. Necrosis is unregulated cell death caused by external factors like infection, trauma or ischemia and results in the premature death of cells and tissue damage
Classification of receptors family by vivek sharmaAnimatedWorld
Definition- Receptor are the biologic molecule to which drug bind and produces a measurable response.
So, enzyme and structural proteins can be considerd to be pharmacologic receptors.
Majorly receptor are of 4 types and the molecule or a drug interact to receptor to give response often called as ligand.
The type of receptor a ligand will bind is depend on the nature of ligand.
Hydrophilliic ligand binds to the receptor found on the cell surface.
Hydrophobic ligand can enter the cell membrane to intract the receptor present on inside the cells.
Classification of Receptors
A. Cell surface receptor
Ligand-gated Ion Channel
G Protein Coupled Receptor
Enzyme linked Receptor
B. Intracellular Receptor
Nuclear Receptor
Alzheimer's disease is a neurological disorder that causes memory loss and cognitive decline. It was first described by Dr. Alois Alzheimer in 1901 when examining patient Auguste D. The causes are not fully understood but involve genetic, environmental, and lifestyle factors. Early signs include memory problems and other cognitive declines. As it progresses, damage occurs in areas controlling language, reasoning, and thought, and patients have trouble recognizing family and friends. By the final stage, plaques and tangles have spread throughout the brain, causing severe impairment and dependence on others for care. While some drugs can temporarily stabilize symptoms, there is no cure for Alzheimer's disease.
The document discusses cell cycle regulation and cell injury. It describes the phases of the cell cycle including G1, S, G2, and M phases. Checkpoints at G1 and G2 regulate progression through the cycle. The cycle is controlled by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Cell injury can be caused by genetic or acquired factors like ischemia, toxins, radiation. Injury may lead to reversible or irreversible damage through effects on mitochondria, membranes, and DNA. Cells undergo programmed cell death through necrosis, apoptosis, or autophagy in response to injury.
This document discusses neurodegenerative diseases and their treatment. It defines neurodegenerative diseases as conditions that primarily affect neurons in the brain, causing problems with movement or mental functioning as neurons are damaged and die. The causes include a buildup of toxic proteins and mitochondrial dysfunction, generally resulting in programmed cell death of neurons. Stroke is also discussed, defined as occurring when a blood vessel blockage or rupture in the brain causes part of the brain to be deprived of oxygen. The two main types of stroke and their symptoms are outlined.
This document discusses various types of mutagenicity tests, including molecular, gene, and chromosomal level tests. It describes three important mutagenicity tests in detail: the Ames test, HPRT gene test, and mouse micronucleus test. The Ames test uses bacteria to identify mutagenic chemicals. The HPRT test detects mutations in the HPRT gene of mammalian cells. The mouse micronucleus test examines mouse bone marrow for evidence of chromosomal damage and mutation. These three tests are commonly used to screen chemicals for potential mutagenicity and carcinogenicity.
My presentation on neurotransmitter glutamate. References from Comprehensive textbook of psychiatry 9th edition and Stahl's essential psychopharmacology 4th edition.
This document discusses GABA (gamma-aminobutyric acid), the primary inhibitory neurotransmitter in the mammalian central nervous system. It outlines GABA's mechanism of action via GABA-A and GABA-B receptors, synthesis, functions in relieving anxiety and improving mood, and relationship to health conditions like insomnia, depression, seizures, and panic disorders when deficient. The conclusion states that GABA functions to inhibit nerve impulses by blocking them, preventing nerve cells from firing too often or easily.
Molecular Mechanisms of Neurodegeneration: Neurodegenerative Disorders Webin...QIAGEN
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.
MAPK Signaling pathway (Mitogen-activated protein kinase), how the pathway helps in regulation of mitosis, It's activation and inactivation inside the cell, roles of MAPK pathway in cancerous cell, different classes of MAP kinase in human
Ion channels are pore-forming membrane proteins that regulate the flow of ions across cell membranes. There are several types of ion channels classified by their gating mechanism and selectivity for specific ions like potassium, sodium, calcium, and chloride. Voltage-gated ion channels open or close in response to changes in membrane potential, while ligand-gated channels are activated by binding of neurotransmitters or other ligands. Ion channels play crucial roles in generating electrical signals in excitable cells and regulating various cellular processes. Diseases caused by mutations in ion channel genes are known as channelopathies.
Pharmacogenomics is the study of how an individual's genetic profile affects their response to medications. It aims to provide the right drug at the right dose for the right patient by understanding genetic factors. Current applications include testing for genetic variants before prescribing certain drugs to avoid bad reactions. Challenges include accounting for both genetic and environmental influences on drug responses and protecting patient privacy. As understanding and technologies improve, pharmacogenomics may help develop new drugs and reduce trial-and-error prescribing.
New treatment trends in alzheimer diseaseSarath Menon
This document summarizes new treatment trends in Alzheimer's disease. It discusses current treatments for mild-moderate Alzheimer's like donepezil, rivastigmine, and galantamine which are cholinesterase inhibitors. Memantine is used for more severe Alzheimer's as an NMDA receptor antagonist. Experimental therapies discussed include vaccines, secretase inhibitors, and stem cell therapy. Lifestyle factors like diet, exercise, and social support are also reviewed for prevention and management of Alzheimer's symptoms.
The document discusses cell signaling pathways and regulation. It describes different types of cell signaling including autocrine, paracrine, synaptic, endocrine, and juxtacrine signaling. It also discusses various signaling molecules like hormones, neurotransmitters, growth factors, and cytokines. The different types of cell surface receptors and intracellular receptors are described, including G protein-coupled receptors, enzyme-linked receptors, and ion channel receptors. The mechanisms of various cell signaling pathways such as G protein signaling and MAP kinase pathways are summarized. Disorders related to improper cell signaling are also mentioned.
Cytochrome P450 enzymes (CYPs) are a large superfamily of heme-containing monooxygenase enzymes that are found in animals, plants, and microorganisms. In humans, CYPs are primarily expressed in the liver and are involved in the metabolism of many medications and toxins. The naming of CYPs indicates the gene family, subfamily, and specific gene. Many drugs are metabolized by CYP enzymes in the liver, with CYP1A2, 2C9, 2C19, 2D6, 3A4, and 3A5 responsible for metabolizing around 90% of clinically used drugs. Variants in CYP genes can result in altered drug metabolism among individuals. Drug
NAD+ and NADH play roles in many important biological processes such as energy metabolism, mitochondrial function, calcium homeostasis, and gene expression. They have emerged as one of the most influential couples in life. Poly (ADP-ribose) polymerase 1 (PARP1) activation leads to NAD+ depletion, which mediates cell death. Intranasal administration of NAD+ can decrease ischemic brain injury by reducing PARP1-induced cell death and is a potential treatment for diseases involving PARP1.
Mitochondrial dysfunction and oxidative damage are thought to play a role in Parkinson's disease (PD) pathogenesis. Recent animal studies show that inhibiting mitochondrial complex I with rotenone closely mimics PD's biochemical and histological features. Several agents like creatine, coenzyme Q10, and acetyl-L-carnitine have shown benefits in animal models by modulating energy metabolism and reducing oxidative stress. These agents warrant further study as potential neuroprotective treatments for PD.
G protein coupled receptors and their Signaling MechanismFarazaJaved
G protein-coupled receptors (GPCRs) are a large family of receptors that span cell membranes and activate intracellular signaling pathways in response to extracellular stimuli. They are activated by a wide range of ligands including light, hormones, and neurotransmitters. Upon ligand binding, GPCRs activate heterotrimeric G proteins, which then initiate intracellular signaling cascades. The three main G protein families - Gs, Gi, and Gq - activate or inhibit different downstream effector enzymes to elicit a cellular response. Dysregulation of GPCRs and their associated signaling pathways can lead to various diseases.
An 80-year-old man presented with symptoms of Alzheimer's disease including memory loss, disorientation, difficulty completing tasks, and mood changes. Brain scans and examination of brain tissue confirmed Alzheimer's disease. Alzheimer's is caused by abnormal accumulation of tau and amyloid-beta proteins in the brain, which form plaques and tangles that damage neurons. It is diagnosed based on symptoms, cognitive tests, and brain imaging, and progresses from mild to severe impairment over time. There are medications to temporarily improve symptoms but no cure for the underlying disease process.
Cytochrome P450 enzymes are important for metabolizing xenobiotics in the body. There are many CYP isoforms located in the liver and intestine that catalyze phase I and phase II reactions to make xenobiotics more hydrophilic for excretion. Phase I reactions like oxidation and hydroxylation introduce reactive or polar groups. Phase II conjugates these compounds with glucuronic acid, glutathione, sulfate, or acetyl groups which greatly increases their water solubility and allows them to be secreted from cells and eliminated from the body. Several drug transporters then efflux the conjugated metabolites out of cells and across barriers to complete their removal from the body. Cytochrome P450 enzymes play a vital role in both the de
Cell death, also known as programmed cell death, occurs through various pathways including apoptosis, autophagy, and necrosis. Apoptosis, or programmed cell death, involves two main pathways - the intrinsic pathway which is triggered by cellular stress and the extrinsic pathway which is triggered by death ligands binding to cell surface death receptors. Both pathways activate caspases that break down cellular components leading to cell death. Autophagy is the natural and regulated mechanism by which cells degrade and recycle unnecessary or dysfunctional cellular components through the formation of autophagosomes and lysosomal degradation. Necrosis is unregulated cell death caused by external factors like infection, trauma or ischemia and results in the premature death of cells and tissue damage
Classification of receptors family by vivek sharmaAnimatedWorld
Definition- Receptor are the biologic molecule to which drug bind and produces a measurable response.
So, enzyme and structural proteins can be considerd to be pharmacologic receptors.
Majorly receptor are of 4 types and the molecule or a drug interact to receptor to give response often called as ligand.
The type of receptor a ligand will bind is depend on the nature of ligand.
Hydrophilliic ligand binds to the receptor found on the cell surface.
Hydrophobic ligand can enter the cell membrane to intract the receptor present on inside the cells.
Classification of Receptors
A. Cell surface receptor
Ligand-gated Ion Channel
G Protein Coupled Receptor
Enzyme linked Receptor
B. Intracellular Receptor
Nuclear Receptor
Alzheimer's disease is a neurological disorder that causes memory loss and cognitive decline. It was first described by Dr. Alois Alzheimer in 1901 when examining patient Auguste D. The causes are not fully understood but involve genetic, environmental, and lifestyle factors. Early signs include memory problems and other cognitive declines. As it progresses, damage occurs in areas controlling language, reasoning, and thought, and patients have trouble recognizing family and friends. By the final stage, plaques and tangles have spread throughout the brain, causing severe impairment and dependence on others for care. While some drugs can temporarily stabilize symptoms, there is no cure for Alzheimer's disease.
The document discusses cell cycle regulation and cell injury. It describes the phases of the cell cycle including G1, S, G2, and M phases. Checkpoints at G1 and G2 regulate progression through the cycle. The cycle is controlled by cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. Cell injury can be caused by genetic or acquired factors like ischemia, toxins, radiation. Injury may lead to reversible or irreversible damage through effects on mitochondria, membranes, and DNA. Cells undergo programmed cell death through necrosis, apoptosis, or autophagy in response to injury.
This document discusses neurodegenerative diseases and their treatment. It defines neurodegenerative diseases as conditions that primarily affect neurons in the brain, causing problems with movement or mental functioning as neurons are damaged and die. The causes include a buildup of toxic proteins and mitochondrial dysfunction, generally resulting in programmed cell death of neurons. Stroke is also discussed, defined as occurring when a blood vessel blockage or rupture in the brain causes part of the brain to be deprived of oxygen. The two main types of stroke and their symptoms are outlined.
This document discusses various types of mutagenicity tests, including molecular, gene, and chromosomal level tests. It describes three important mutagenicity tests in detail: the Ames test, HPRT gene test, and mouse micronucleus test. The Ames test uses bacteria to identify mutagenic chemicals. The HPRT test detects mutations in the HPRT gene of mammalian cells. The mouse micronucleus test examines mouse bone marrow for evidence of chromosomal damage and mutation. These three tests are commonly used to screen chemicals for potential mutagenicity and carcinogenicity.
My presentation on neurotransmitter glutamate. References from Comprehensive textbook of psychiatry 9th edition and Stahl's essential psychopharmacology 4th edition.
This document discusses GABA (gamma-aminobutyric acid), the primary inhibitory neurotransmitter in the mammalian central nervous system. It outlines GABA's mechanism of action via GABA-A and GABA-B receptors, synthesis, functions in relieving anxiety and improving mood, and relationship to health conditions like insomnia, depression, seizures, and panic disorders when deficient. The conclusion states that GABA functions to inhibit nerve impulses by blocking them, preventing nerve cells from firing too often or easily.
Molecular Mechanisms of Neurodegeneration: Neurodegenerative Disorders Webin...QIAGEN
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.
MAPK Signaling pathway (Mitogen-activated protein kinase), how the pathway helps in regulation of mitosis, It's activation and inactivation inside the cell, roles of MAPK pathway in cancerous cell, different classes of MAP kinase in human
Ion channels are pore-forming membrane proteins that regulate the flow of ions across cell membranes. There are several types of ion channels classified by their gating mechanism and selectivity for specific ions like potassium, sodium, calcium, and chloride. Voltage-gated ion channels open or close in response to changes in membrane potential, while ligand-gated channels are activated by binding of neurotransmitters or other ligands. Ion channels play crucial roles in generating electrical signals in excitable cells and regulating various cellular processes. Diseases caused by mutations in ion channel genes are known as channelopathies.
Pharmacogenomics is the study of how an individual's genetic profile affects their response to medications. It aims to provide the right drug at the right dose for the right patient by understanding genetic factors. Current applications include testing for genetic variants before prescribing certain drugs to avoid bad reactions. Challenges include accounting for both genetic and environmental influences on drug responses and protecting patient privacy. As understanding and technologies improve, pharmacogenomics may help develop new drugs and reduce trial-and-error prescribing.
New treatment trends in alzheimer diseaseSarath Menon
This document summarizes new treatment trends in Alzheimer's disease. It discusses current treatments for mild-moderate Alzheimer's like donepezil, rivastigmine, and galantamine which are cholinesterase inhibitors. Memantine is used for more severe Alzheimer's as an NMDA receptor antagonist. Experimental therapies discussed include vaccines, secretase inhibitors, and stem cell therapy. Lifestyle factors like diet, exercise, and social support are also reviewed for prevention and management of Alzheimer's symptoms.
The document discusses cell signaling pathways and regulation. It describes different types of cell signaling including autocrine, paracrine, synaptic, endocrine, and juxtacrine signaling. It also discusses various signaling molecules like hormones, neurotransmitters, growth factors, and cytokines. The different types of cell surface receptors and intracellular receptors are described, including G protein-coupled receptors, enzyme-linked receptors, and ion channel receptors. The mechanisms of various cell signaling pathways such as G protein signaling and MAP kinase pathways are summarized. Disorders related to improper cell signaling are also mentioned.
Cytochrome P450 enzymes (CYPs) are a large superfamily of heme-containing monooxygenase enzymes that are found in animals, plants, and microorganisms. In humans, CYPs are primarily expressed in the liver and are involved in the metabolism of many medications and toxins. The naming of CYPs indicates the gene family, subfamily, and specific gene. Many drugs are metabolized by CYP enzymes in the liver, with CYP1A2, 2C9, 2C19, 2D6, 3A4, and 3A5 responsible for metabolizing around 90% of clinically used drugs. Variants in CYP genes can result in altered drug metabolism among individuals. Drug
NAD+ and NADH play roles in many important biological processes such as energy metabolism, mitochondrial function, calcium homeostasis, and gene expression. They have emerged as one of the most influential couples in life. Poly (ADP-ribose) polymerase 1 (PARP1) activation leads to NAD+ depletion, which mediates cell death. Intranasal administration of NAD+ can decrease ischemic brain injury by reducing PARP1-induced cell death and is a potential treatment for diseases involving PARP1.
Mitochondrial dysfunction and oxidative damage are thought to play a role in Parkinson's disease (PD) pathogenesis. Recent animal studies show that inhibiting mitochondrial complex I with rotenone closely mimics PD's biochemical and histological features. Several agents like creatine, coenzyme Q10, and acetyl-L-carnitine have shown benefits in animal models by modulating energy metabolism and reducing oxidative stress. These agents warrant further study as potential neuroprotective treatments for PD.
Autophagy and Mitophagy in CNS disordersAditya Singh
Mitophagy and autophagy are important cellular processes for the degradation and recycling of damaged mitochondria and proteins. Imbalances in these processes can lead to neurodegeneration as seen in diseases like Parkinson's and Alzheimer's. Several receptors are involved in mitophagy, and mutations affecting the PINK1/Parkin pathway have been linked to Parkinson's disease by impairing mitophagy. Both autophagy and mitophagy are impaired in Alzheimer's disease, contributing to mitochondrial dysfunction, oxidative stress, and the accumulation of amyloid plaques and tau tangles. Enhancing these degradation pathways through pharmacological interventions may offer therapeutic strategies for neurodegenerative conditions.
1. The document discusses research into how inhibition of TXNRD or SOD1 can overcome resistance to β-lapachone that is mediated by NRF2. Stable cell lines were generated for experiments using lentiviral transduction.
2. Western blot and fluorescence techniques were used to analyze protein expression and localization. Nuclear isolation was also utilized. Results showed that overexpression of KEAP1 or NRF2 led to resistance to β-lapachone. Silencing NRF2 reduced this resistance.
3. Depletion of catalase did not affect β-lapachone sensitivity, but inhibition of TXNRD with auranofin increased DNA damage and cell death in response to β-lap
The document discusses the relationship between mitochondrial dysfunction and Parkinson's disease (PD). It summarizes that neurotoxins like MPTP can induce PD by decreasing the activity of mitochondrial Complex I, which is involved in cellular respiration. This reduction in Complex I activity leads to increased oxidative stress and apoptosis of dopaminergic neurons. While certain genetic polymorphisms and calcium accumulation may also contribute to mitochondrial dysfunction, neurotoxins appear to be a primary factor in reducing Complex I activity and inducing PD.
Mitochondrial Dysfunctional Activity and the relationship with PDCarlos Santos Perez
The document discusses the relationship between mitochondrial dysfunction and Parkinson's disease (PD). It summarizes that neurotoxins like MPTP can induce PD by decreasing the activity of mitochondrial Complex I, which is involved in cellular respiration. This reduction in Complex I activity leads to increased oxidative stress and apoptosis of dopaminergic neurons. While certain genetic polymorphisms and calcium accumulation may also contribute to mitochondrial dysfunction, neurotoxins appear to be a primary factor in reducing Complex I activity and inducing PD.
Mitochondrial dysfunctional activity and relationship with pdCarlos Santos Perez
The document discusses the relationship between mitochondrial dysfunction and Parkinson's disease (PD). It summarizes that neurotoxins like MPTP can induce PD by decreasing the activity of mitochondrial Complex I, which is involved in cellular respiration. This reduction in Complex I activity leads to increased oxidative stress and apoptosis of dopaminergic neurons. While certain genetic polymorphisms and calcium accumulation may also contribute to mitochondrial dysfunction, neurotoxins appear to be a primary factor in reducing Complex I activity and inducing PD.
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
The document discusses various topics related to DNA methylation and its roles in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
This document discusses various topics related to DNA methylation and its roles in human pathology. It begins by describing the MeCP2 protein and Rett syndrome, where mutations in the MECP2 gene cause the condition. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can cause genome instability and gene silencing. Finally, it examines the roles of DNA methyltransferases and histone deacetylases, and how inhibitors of these enzymes show promise as epigenetic cancer therapies.
The document discusses various topics related to DNA methylation and its role in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
The document discusses various topics related to DNA methylation and its role in human pathology. It begins by describing the MeCP2 protein and its involvement in Rett syndrome through mutations in the MECP2 gene. It then discusses how alterations in DNA methylation levels and patterns are common in cancer and can lead to genomic instability. Finally, it examines the use of epigenetic therapies like DNA methyltransferase inhibitors and histone deacetylase inhibitors to treat cancer by reversing aberrant DNA methylation and histone modifications.
This research article examines the role of proteasome activator proteins PA28α and PA28β in the development of microvascular injury in diabetic nephropathy and retinopathy. The researchers found that genetically deleting the PA28α and PA28β genes in mice protected against renal injury and retinal damage caused by diabetes. In cell and tissue samples from these mice, the expression of inflammatory proteins like osteopontin and MCP-1 were reduced under high glucose conditions. The findings suggest that diabetic hyperglycemia increases PA28 activity in vulnerable kidney and eye cells, leading to microvascular damage through altered proteasome function and increased inflammation. Targeting the PA28 pathway may help prevent complications from diabetic nephro
Decreases Expression of PGC-1α in the Alzheimer Disease Brain Impaire Mitocho...rana alhakimi
Alzheimer is the most neurodegenerative disorder in the aged people. It is characterized by senile, accumulation of amyloid plaque, neurofibrillary tangle and progressive decline in brain memory cells.
Alzheimer disease is associated with inflammatory response, synaptic damage and mitochondrial dysfunctions which are a prominent and early feature of Alzheimer disease.
Free radicals in Neurodegenerative diseases- Parkinsonism.pptxE Poovarasan
This document discusses the role of free radicals in neurodegenerative diseases. It states that free radicals significantly contribute to neuronal cell deterioration by damaging biomolecules like DNA, RNA, lipids and proteins. This leads to diseases like Parkinson's, Alzheimer's and Huntington's. Parkinson's disease is characterized by dopamine neuron death and is linked to increased free radical production from dopamine oxidation and iron accumulation. Oxidative stress also contributes to protein aggregation and mitochondrial dysfunction in neurodegeneration. The document summarizes the mechanisms of free radical damage in several major neurodegenerative diseases.
This document discusses mitochondrial mechanisms of brain injury and potential neuroprotective interventions. It summarizes that mitochondrial dysfunction, oxidative stress, and apoptosis are key mechanisms of brain injury. Various interventions are proposed to target these mechanisms, including reducing oxidative stress through Nrf2 activators like sulforaphane, protecting bioenergetics through alternative fuels or PTP inhibitors, and modulating apoptosis. In vitro and animal studies provide evidence that compounds like sulforaphane, acetyl-L-carnitine, and cyclosporin A may confer neuroprotection through these mitochondrial mechanisms.
This document discusses the pharmacology of antiparkinsonian drugs. It begins by defining Parkinson's disease as a neurodegenerative disorder characterized by bradykinesia, rigidity, and tremor. The primary deficit is degeneration of neurons in the substantia nigra. Current treatments aim to replace dopamine or stimulate dopamine receptors in the brain. Drugs discussed include levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, and anticholinergics. The document also summarizes recent research on cortical thinning patterns and dietary fat intake in Parkinson's disease patients.
1. The document discusses complex I, the first enzyme in the mitochondrial electron transport chain. It has 45 subunits encoded by both nuclear and mitochondrial DNA. Deficiencies in complex I can cause various mitochondrial diseases.
2. The lab studies complex I structure and assembly using three mouse fibroblast cell lines: A9 (normal complex I), 4A (mutated ND6 gene impairing complex I), and 4AR (restored complex I despite ND6 mutation). They use gel electrophoresis, western blotting, and co-immunoprecipitation to analyze complex I proteins.
3. Defects in mitochondrial complex I subunits can lead to diseases like Parkinson's, cancers, and neurological/my
Mitochondrial DNA encodes 13 proteins that are essential components of the oxidative phosphorylation system for producing cellular energy. Over 100 mutations in mitochondrial DNA have been linked to human disease. Mitochondrial DNA is inherited maternally and diseases often involve the muscles, brain, or both. Presentation can occur at any age and involves a variety of neurological or systemic symptoms depending on the mutation. Diagnosis involves clinical evaluation, blood or tissue analysis, and imaging or biopsy. Treatment focuses on supporting affected systems; more targeted therapies are under development.
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4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
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2. Parkinson’s disease
• Neuro degenerative disease.
• It predominantly affects the dopamine
secreting neurons in particular the substantia
nigra.
• mitochondrial complex 1 dysfunction is said to
contributing to parkinsonism.
PATHWAY AFFECTED
Nigrostriatal tract
INTRODUCTION
2
https://doi.org/10.3389/fnbeh.2016.00121
blueringmedia
3. MITOCHONDRIA and its structure
IN MITOCHONDRIAL MATRIX
NADH passes through complex 1,electrons thus produced
creates a protein gradient and thereby, ATP by oxidative
phosphorylation
TCA CYCLE
Pyruvate converted to acetyl coA which are then converted to
NADH and FAD
GLYCOLYSIS
Releases 2 pyruvate
3
Mohamed Yusoff, Abdul Aziz. (2015). Understanding Mitochondrial DNA in Brain Tumorigenesis.
4. ELECTRON TRANSPORT CHAIN
MECHANISM
Bailey, Regina. "Electron Transport Chain and Energy Production Explained." ThoughtCo, Feb. 7, 2021, thoughtco.com/electron-transport-chain-and-energy-production-4136143. 4
Hovde, Blake & Deodato, Chloe & Andersen, Robert & Starkenburg, Shawn & Barlow, Steven & Cattolico, Rose Ann. (2019). Chrysochromulina: Genomic assessment and taxonomic diagnosis of the type species for an oleaginous algal
clade. Algal Research. 37. 307-319. 10.1016/j.algal.2018.11.023.
5. COMPLEX-1
Metabolic role of complex 1 is to oxidize NADH to NAD+ where 2 electrons are released 4 protons are released into
inter membrane space
STRUCTURE AND ARCHITECHTURE
▪ L-shaped structure and has 45 subunits
SUPER NUMERARY SUBUNITS—protectIon from ROS
NADH UBIQUINONE OXIDOREDUCTASE
SUB UNITS
N-module P-module Q-module
31 –super
numerary
14 core
-----
-----
HYDROPHILIC
HYDROPHOBIC
Rutger O. Vogel, Jan A.M. Smeitink, Leo G.J. Nijtmans,Human mitochondrial complex I assembly: A dynamic and versatile process,Biochimica et Biophysica Acta (BBA) - Bioenergetics
5
6. 854M. Mimaki et al. / Biochimica et Biophysica Acta 1817 (2012) 851–862
FORMATION OF MITOCHONDRIAL COMPLEX-1
6
https://doi.org/10.1016/j.bbabio.2007.07.008
7. N-module
Q-module
P-module
• Dehydrogenase module
• Binds to NADH,captures electrons from oxidation
of NADH
• Hydrogenase module
• Electron transfer to ubiquinone
• Proton translocation module
• Binding of ubiquinone and proton pumping
FUNCTIONS OF SUBUNITS IN COMPLEX 1
• NDUFA9—Harbours NADH binding site
• ND1-provides protection from oxidative stress
7
8. Mt DNA
encoded sub
units
NUCLEAR DNA
Encoded sub
units
ND1
ND2
ND3
ND4
ND4L
ND5
ND6
NDUFV1
NDUFV2
NDUFS1
NDUFS2
NDUFS3
NDUFS7
NDUFS8
MITOCHONDRIAL c1 SUBUNIT DEFECTS THAT LEAD
TO DYSFUNCTION
NDUFV1 defect- causes hypersensitivity to oxidative stress
ND1 &ND5 deficiency-causes idiopathic parkinsonism
Hovde, Blake & Deodato, Chloe & Andersen, Robert & Starkenburg, Shawn & Barlow, Steven & Cattolico, Rose Ann. (2019). Chrysochromulina: Genomic assessment and taxonomic diagnosis of the type species
for an oleaginous algal clade. Algal Research. 37. 307-319. 10.1016/j.algal.2018.11.023.
8
9. COMPLEX 1 INVOLVEMENT IN PD
• In parkinsons disease nearly 42% of complex 1 dysregulation
occurs in mitochondria of substantia nigra
Majority of complex1 deficiency
occurs due to mutations in
genes such as
•
•
•
•
•
•
•
•
•
Compagnoni, Giacomo & Di Fonzo, Alessio & Corti, Stefania & Comi, Giacomo & Bresolin, Nereo & Masliah, Eliezer. (2020). The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer’s Disease and Parkinson’s Disease. Molecular
Neurobiology. 57. 10.1007/s12035-020-01926-1.
9
10. EVIDENCES OF OXIDATIVE DAMAGE AT COMPLEX1
• In a research study brains are isolated from dead bodies of individuals where one of them suffers with
parkinsons disease
PATHOLOGICALLY
CONFIRMEDCONTROL
BRAIN
PARKINSONS BRAIN
Normal catalysis of NADH
at complex1
Decreased catalytic activity of
complex1
No change in level No change in levels
No significant change showed 11% increase in 20kda
protein and 33% reduction in 8kda
proteins compared to normal brain
LESS or No significant
amount
47% more when compared to normal
individuals
Proteins of
complexes 2-4
ND6 protein
Protein carbonyls
Paula M. Keeney, Jing Xie, Roderick A. Capaldi and James P. Bennett Jr Journal of Neuroscience 10 May 2006, 26 (19) 5256-5264; DOI: https://doi.org/10.1523/JNEUROSCI.0984-06.2006
10
11. • SO from the study it was found that there is a negative correlation between oxidative damage and
8Kda subunits of complex1
• Subunits that mainly suffer oxidative damage in complex1 are
Mt-DNA encoded subunits NuclearDNA encoded subunits
ND4
ND5
NDUFS1
NDUFS2
NDUFV1
NDUFB2
NDUFB6
NDUFB7
11
12. FUNCTIONS IMPAIRED
MITOCHONDRIAL C1
DYSFUNCTION
Increased oxidative stress
Reduced oxidative stress
response
Reduced ATP
production
Decreased UPS
function
Weak excitotoxicity
and increased free
radicles
APOPTOSIS
Grünewald, Anne & Kumar, Kishore & Sue, Carolyn. (2018). New insights into the complex role of mitochondria in Parkinson’s disease. Progress in Neurobiology. 177. 10.1016/j.pneurobio.2018.09.003.
12
14. MITO PARK MODEL:
Based on inactivation of MT transcription factor Tfam.
NUCLEAR GENOME Tfam gene Disruption
corresponding protein is imported to
mitochondria
DNA binding protein and aslo essential for
transcriptiom and maintainance of MT DNA
Decreased mt respiration
and respiratory chain
failure
1
Ekstrand, M. I., & Galter, D. (2009). The MitoPark Mouse - an animal model of Parkinson's disease with impaired respiratory chain function in dopamine neurons. Parkinsonism & related disorders, 15 Suppl 3, S185–S188.
https://doi.org/10.1016/S1353-8020(09)70811-9 14
15. CHEMICALLY INDUCED MODEL
MPTP treated mice model -
Heikkila et al., 1984, 1985; Markey et al., 1984; Javitch et al., 1985; Ramsey et al., 1986; Vays et al... 1986, Di Monte et al., 1986, Mizuno et al., 1987: Chiba et al 1988, Hasegawa, 1990, Cui et al., 2009..
15
16. MPP at complex 1
prevents electron
flow to further
complexes
Electron
accumulation and
tranfered to mol
oxygen
ROS production
and oxidative
stress
Protein gradient
disturbance
ATPase inactivation
ENERGY CRISIS
16
Nicklas et al., 1985; Ramsay et al., 1986;Mizuno et al., 1987.
17. This research provided data that progressive loss of MC1 function in dopa neurons trigger progressive and levodopa responsive
parkinsonism which occurred only when somstodendric SNDA fell
Slow loss of MC1 function caused NDFSU2 deletion caused warberg shift but bioenergetic demands of SN can be met by OXPHOS which
was found to be declined by ageing.
.
https://doi.org/10.1038/s41586-021-04059-010.1038/s41586-021-04059- González-Rodríguez2021 17
18. A metabolomic analysis of the plasma was made from a mouse model of prodromal PD (p-PD). Increased levels
of isobutyrylcarnitine in p-PD mice show an abnormality in β-oxidation in mitochondria
Increased levels of pyrimidine nucleoside can be associated with mitochondrial dysfunction. Consistent with
these results, the immunoblot analysis showed a defect in mitochondrial complex I assembly in p-PD mice.
Masashi Ikuno, Hodaka Yamakado, Ikuko Amano, Yusuke Hatanaka, Norihito Uemura, Shu-ichi Matsuzawa, Ryosuke Takahashi,Mitochondrial dysfunction in a mouse model of prodromal Parkinson’s disease: A
metabolomic analysis,Neuroscience Letters,Volume765,2021,136267,ISSN 0304-3940,https://doi.org/10.1016/j.neulet.2021.136267 18
19. https://doi.org/10.1155/2021/557754110.1155/2021/5577541 Oxidative Medicine and Cellular Longevity
Oxidation of cardiolipin in the substantia nigra is enhanced by rotenone, an inhibitor of complex I, in a model of PD so ,inhibition
of cardiolipin oxidation allows a correct functioning of the mitochondria.
Adequate levels of cardiolipin are crucial for efficient electron transport between CoQ and complex, maintain normal
mitochondrial cristae structure and correct assembly of the electron chain supercomplexes
melatonin resulted in a significant reduction of oxidative stress markers. significant increases of catalase, complex I activity, and
respiratory control , prevents cardiolipin loss and oxidation which avoids mitochondrial membrane permeabilization induced by
reactive oxygen species and other factors
19
20. THERAPEUTIC
OPTIONS
MPPE
Urso
deoxycholic
acid
metformin
Niacin
MAO-B inhibitor
• Prevents MPTP induced
neural loss by
upregulating Super
oxide dismutase
o Beneficial for treating
LRRK2 mutation
o Protection against toxic
and genetic forms of PD
20
Anne Grünewald, Kishore R. Kumar, Carolyn M. Sue,New insights into the complex role of mitochondria in Parkinson’s disease,Progress in Neurobiology,Volume 177,2019,Pages 73-93,ISSN 0301-
0082,https://doi.org/10.1016/j.pneurobio.2018.09.003.
Decreases the ROS
production at mc1 by
reverse electron
transfer
Binds to
GPR109A
that provide
protection
from MPP+
22. CONCLUSION
So on a final note we can conclude that complex 1 dysfunction undergoes oxidative damage
particularly in NDFSU2 and few subunits of N module lead to a progressive loss of function .
Warberg shift type of remodeling for decreasing energy requirements.In a metabolomic analysis of
predromic mice increased levels pyridine nucleoside levels found explaining defect in MC1.
It was also found that cardiolipin level disturbances also causes dysfunction in complex 1 activity there
by contributing to PD.Mutations in genes such as Tfam, LRRK2,PGC1alpha, and external factors such
as MPP ,rotenone also lead to functional dysfunction of Mitochondrial complex 1 causing disturbance
in energitics and increase in ROS that ultimately causing cell death
22
23. REFERENCES
1. Gzálezon-Rodríguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, Tkatch T, Stavarache MA, Wokosin DL, Gao L, Kaplitt
MG, López-Barneo J, Schumacker PT, Surmeier DJ. Disruption of mitochondrial complex I induces progressive parkinsonism.
Nature. 2021 Nov;599(7886):650-656. doi: 10.1038/s41586-021-04059-0. Epub 2021 Nov 3. PMID: 34732887.
2. Subrahmanian N, LaVoie MJ. Is there a special relationship between complex I activity and nigral neuronal loss in Parkinson's
disease? A critical reappraisal. Brain Res. 2021 Sep 15;1767:147434. doi: 10.1016/j.brainres.2021.147434. Epub 2021 Mar 19.
PMID: 33745923.
3. Christophe Wirth, Ulrich Brandt, Carola Hunte, Volker Zickermann,Structure and function of mitochondrial complex I,Biochimica et
Biophysica Acta (BBA) - Bioenergetics,Volume 1857, Issue 7,2016,Pages 902-914,ISSN 0005-
2728https://doi.org/10.1016/j.bbabio.2016.02.013
4. Masakazu Mimaki, Xiaonan Wang, Matthew McKenzie, David R. Thorburn, Michael T. Ryan,Understanding mitochondrial complex I
assembly in health and disease Biochimica et Biophysica Acta (BBA) - Bioenergetics,Volume 1817, Issue 6,2012,Pages 851-
862,ISSN 0005-2728,https://doi.org/10.1016/j.bbabio.2011.08.010.
5. Ekstrand MI, Galter D. The MitoPark Mouse - an animal model of Parkinson's disease with impaired respiratory chain function in
dopamine neurons. Parkinsonism Relat Disord. 2009 Dec;15 Suppl 3:S185-8. doi: 10.1016/S1353-8020(09)70811-9. PMID:
20082987.
6. Keeney PM, Xie J, Capaldi RA, Bennett JP Jr. Parkinson's disease brain mitochondrial complex I has oxidatively damaged subunits
and is functionally impaired and misassembled. J Neurosci. 2006 May 10;26(19):5256-64. doi: 10.1523/JNEUROSCI.0984-06.2006.
PMID: 16687518; PMCID: PMC6674236.
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