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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Mitochondria-targeted antioxidants for treatment of Parkinson's disease: Preclinical and clinical outcomes

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2013, Volume and Issue: 1842(8), P. 1282 - 1294

Published: Sept. 20, 2013

Language: Английский

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Mitochondria and Reactive Oxygen Species in Aging and Age-Related Diseases

International review of cell and molecular biology, Journal Year: 2018, Volume and Issue: unknown, P. 209 - 344

Published: Jan. 1, 2018

Language: Английский

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Mitochondrial Quality Control and Disease: Insights into Ischemia-Reperfusion Injury

Molecular Neurobiology, Journal Year: 2017, Volume and Issue: 55(3), P. 2547 - 2564

Published: April 11, 2017

Mitochondria are key regulators of cell fate during disease. They control survival via the production ATP that fuels cellular processes and, conversely, death induction apoptosis through release pro-apoptotic factors such as cytochrome C. Therefore, it is essential to have stringent quality mechanisms ensure a healthy mitochondrial network. Quality largely regulated by dynamics and mitophagy. The fission (division) fusion allow for damaged mitochondria be segregated facilitate equilibration components DNA, proteins, metabolites. process mitophagy responsible degradation recycling mitochondria. These been well studied in chronic acute pathologies Parkinson's disease, Alzheimer's stroke, myocardial infarction, but less known about how these two interact contribute specific pathophysiologic states. To date, evidence role disease divergent suggests can serve both functions depending on state. This review aims provide synopsis molecular involved control, summarize our current understanding complex plays progression vs diseases finally, speculate possibility targeted manipulation may exploited rationale design novel therapeutic interventions.

Language: Английский

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Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease

Human Molecular Genetics, Journal Year: 2012, Volume and Issue: 21(23), P. 5131 - 5146

Published: Aug. 27, 2012

The purpose of our study was to determine the relationship between voltage-dependent anion channel 1 protein (VDAC1) and amyloid beta (Aβ) phosphorylated tau in Alzheimer's disease (AD). Using brain specimens from AD patients, control subjects 6-, 12- 24-month-old Aβ precursor (APP) transgenic mice, we studied VDAC1 levels. Further, also interaction (monomers oligomers) tau, using cortical issues subjects, APP, APP/PS1 3XTg.AD mice. We age- VDAC1-linked, mutant APP/Aβ-induced mitochondrial dysfunction APP non-transgenic wild-type (WT) found progressively increased levels tissues brains patients with AD, relative significantly cerebral cortices age-matched WT Interestingly, interacted mice These observations led us conclude that interacts Aβ, may turn block pores, leading pathogenesis. Based on current observations, propose reduced VDAC1, reduce abnormal tau; maintain normal pore opening closure, ultimately function, mitochondria supplying ATP nerve terminals boosting synaptic cognitive function AD.

Language: Английский

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