Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage

Human Molecular Genetics, Journal Year: 2011, Volume and Issue: 20(13), P. 2495 - 2509

Published: March 31, 2011

The purpose of our study was to better understand the relationship between mitochondrial structural proteins, particularly dynamin-related protein 1 (Drp1) and amyloid beta (Aβ) in progression Alzheimer's disease (AD). Using qRT-PCR immunoblotting analyses, we measured mRNA levels genes frontal cortex patients with early, definite severe AD control subjects. We also characterized monomeric oligomeric forms Aβ these patients. immunoprecipitation/immunoblotting analysis, investigated interaction Drp1. immunofluorescence determined localization Drp1 intraneuronal brains primary hippocampal neurons from precursor (AβPP) transgenic mice. found increased expression fission Fis1 (fission 1) decreased fusion Mfn1 (mitofusin 1), Mfn2 2), Opa1 (optic atrophy Tomm40. matrix gene CypD up-regulated Results analyses suggest that abnormal dynamics increase as progresses. Immunofluorescence analysis antibody antibodies 6E10 A11 revealed colocalization Aβ. interacts monomers oligomers patients, interactions are progression. Primary were accumulated had lost branches degenerated, indicating may cause neuronal degeneration. These findings AD, production crucial factors fragmentation, synaptic damage. Inhibiting, be a therapeutic strategy reduce damage cognitive decline AD.

Language: Английский

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Mitochondrial Dysfunction in Neurodegenerative Diseases

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2012, Volume and Issue: 342(3), P. 619 - 630

Published: June 13, 2012

Neurodegenerative diseases are a large group of disabling disorders the nervous system, characterized by relative selective death neuronal subtypes. In most cases, there is overwhelming evidence impaired mitochondrial function as causative factor in these diseases. More recently, has emerged for dynamics (shape, size, fission-fusion, distribution, movement etc.) neurodegenerative such Parkinson9s disease, Huntington9s amyotrophic lateral sclerosis, and Alzheimer9s disease. Here, we provide concise overview major findings recent years highlighting importance healthy mitochondria neuron.

Language: Английский

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Disturbed mitochondrial dynamics and neurodegenerative disorders

Nature Reviews Neurology, Journal Year: 2014, Volume and Issue: 11(1), P. 11 - 24

Published: Dec. 9, 2014

Language: Английский

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Mitochondria: The Next (Neurode)Generation

Neuron, Journal Year: 2011, Volume and Issue: 70(6), P. 1033 - 1053

Published: June 1, 2011

Language: Английский

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Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage

Human Molecular Genetics, Journal Year: 2012, Volume and Issue: 21(11), P. 2538 - 2547

Published: Feb. 24, 2012

We recently reported increased mitochondrial fission and decreased fusion, amyloid beta (Aβ) interaction with the protein Drp1, fragmentation, impaired axonal transport of mitochondria synaptic degeneration in neurons affected by AD. In present study, we extended our previous investigations to determine whether phosphorylated tau interacts Drp1 elucidate damage progression also investigated GTPase activity, which is critical for postmortem brain tissues from patients AD APP, APP/PS1 3XTg.AD mice. Using co-immunoprecipitation immunofluorescence analyses, first time, demonstrated physical between Drp1. Mitochondrial fission-linked activity was significantly elevated frontal cortex cortical On basis these findings, conclude that Aβ tau, likely leading excessive deficiencies, ultimately possibly neuronal cognitive decline. Treatment designed reduce expression and/or may decrease Aβ, conferring protection toxic insults tau.

Language: Английский

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Mitochondrial dynamics in health and disease: mechanisms and potential targets

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 6, 2023

Abstract Mitochondria are organelles that able to adjust and respond different stressors metabolic needs within a cell, showcasing their plasticity dynamic nature. These abilities allow them effectively coordinate various cellular functions. Mitochondrial dynamics refers the changing process of fission, fusion, mitophagy transport, which is crucial for optimal function in signal transduction metabolism. An imbalance mitochondrial can disrupt function, leading abnormal fate, range diseases, including neurodegenerative disorders, cardiovascular diseases cancers. Herein, we review mechanism dynamics, its impacts on function. We also delve into changes occur during health disease, offer novel perspectives how target modulation dynamics.

Language: Английский

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Mitochondrial Diseases of the Brain

Free Radical Biology and Medicine, Journal Year: 2013, Volume and Issue: 63, P. 1 - 29

Published: April 6, 2013

Language: Английский

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Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(10), P. 529 - 546

Published: Aug. 14, 2020

Language: Английский

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LRRK2 regulates mitochondrial dynamics and function through direct interaction with DLP1

Human Molecular Genetics, Journal Year: 2012, Volume and Issue: 21(9), P. 1931 - 1944

Published: Jan. 6, 2012

The leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of autosomal-dominant Parkinson disease (PD). Mitochondrial dysfunction represents a critical event in pathogenesis PD. We demonstrated that wild-type (WT) LRRK2 expression caused mitochondrial fragmentation along with increased dynamin-like protein (DLP1, also known as DRP1), fission protein, which was further exacerbated by PD-associated mutants (R1441C or G2019S) both SH-SY5Y and differentiated primary cortical neurons. found interacted DLP1, LRRK2–DLP1 interaction enhanced probably results DLP1 levels. Co-expression dominant-negative K38A WT Mfn2 blocked LRRK2-induced fragmentation, neuronal toxicity. Importantly, were not observed cells expressing either GTP-binding deficient mutant K1347A kinase-dead D1994A has minimal did increase level. concluded regulates dynamics increasing through its direct activity plays role this process.

Language: Английский

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Mutant huntingtin's interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington's disease

Human Molecular Genetics, Journal Year: 2011, Volume and Issue: 21(2), P. 406 - 420

Published: Oct. 13, 2011

The purpose of this study was to investigate the link between mutant huntingtin (Htt) and neuronal damage in relation mitochondria Huntington's disease (HD). In an earlier study, we determined relationship Htt mitochondrial dynamics/synaptic viability HD patients. We found loss, abnormal dynamics association with current sought expand on our previous findings further elucidate synaptic deficiencies. hypothesized that Htt, mitochondria, alters dynamics, leading fragmentation defective axonal transport neurons. using postmortem brains primary neurons from transgenic BACHD mice, identified interaction protein Drp1 factors cause including GTPase enzymatic activity. Further, for first time, studied degeneration. also investigated effect aggregates oligomers deficiencies mice. interacts Drp1, elevates activity, increases results anterograde movement These observations support hypothesis provide data can be utilized develop therapeutic targets are capable inhibiting decreasing fragmentation, enhancing protecting synapses toxic insults caused by Htt.

Language: Английский

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