Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 20, Issue -, Pages S325-S334Publisher
IOS PRESS
DOI: 10.3233/JAD-2010-100363
Keywords
Autophagy; calcium dysregulation; electron transport chain; 1-methyl-4-phenylpyridinium (MPP plus ); mitochondria; mitophagy; neurodegeneration; oxidative stress; Parkinson's disease; PTEN-induced kinase 1
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Funding
- National Institutes of Health [AG026389, AG026389-03S109, NS059806-01A26235]
- Ellison Medical Foundation
- American Parkinson Disease Association
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [P01NS059806] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG026389] Funding Source: NIH RePORTER
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It is clear from a striking convergence of human tissue studies, neurotoxin models, and genetic models that mitochondrial dysregulation plays a central pathogenic role in Parkinson's disease (PD) and related neurodegenerative conditions. Impaired mitochondrial quality could result from both increased damage and decreased ability to repair or clear damaged mitochondria. In particular, common deficits in mitochondrial respiratory chain function, oxidative stress, morphology/dynamics, and calcium handling capacities have been described in multiple PD model systems employing complex I inhibitors, 6-hydroxydopamine and molecular manipulation of Parkinsonian genes including alpha-synuclein, PTEN-induced kinase I, Parkin, DJ-1, and, to a lesser extent, leucine rich repeat kinase 2. The most recent and exciting work implicates alterations in the regulation of macroautophagy and likely of selective mitophagic clearance of damaged mitochondria, although additional studies are needed to resolve some issues in this area. Future studies emphasizing the normal mitoprotective function(s) of proteins associated with recessive loss-of-function causes of familial PD, as well as compensatory mechanisms operating in their absence, may offer particularly valuable insights into strategies to enhance mitochondrial health.
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