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Nuclear genes associated with mitochondrial DNA processes as contributors to Parkinson's Disease risk

Müller‐Nedebock, A.C., Westhuizen, F.H., Kõks, S. and Bardien, S. (2021) Nuclear genes associated with mitochondrial DNA processes as contributors to Parkinson's Disease risk. Movement Disorders . Early View.

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Over the past four decades, mitochondrial dysfunction has been a recurring theme in Parkinson's disease (PD) and is hypothesized to play a central role in its disease pathogenesis. Given the instrumental role of mitochondria in cellular energy production, their dysfunction can be detrimental to highly energy‐dependent dopaminergic neurons, known to degenerate in PD. Mitochondria harbor multiple copies of their own genomes (mtDNA), encoding critical respiratory chain complexes required for energy production. Consequently, mtDNA has been investigated as a source of mitochondrial dysfunction in PD. As seen in multiple mitochondrial diseases, deleterious mtDNA variation and mtDNA copy number depletion can impede mtDNA protein synthesis, leading to inadequate energy production in affected cells and the onset of a disease phenotype. As such, high burdens of mtDNA defects but also mtDNA depletion, previously identified in the substantia nigra of PD patients, have been suggested to play a role in PD. Genetic variation in nuclear DNA encoding factors required for replicating, transcribing, and translating mtDNA, could underlie these observed mtDNA changes. Herein we examine this possibility and provide an overview of studies that have investigated whether nuclear‐encoded genes associated with mtDNA processes may influence PD risk. Overall, pathway‐based analysis studies, mice models, and case reports of mitochondrial disease patients manifesting with parkinsonism all implicate genes encoding factors related to mtDNA processes in neurodegeneration and PD. Most notably, cumulative genetic variation in these genes likely contributes to neurodegeneration and PD risk by acting together in common pathways to disrupt mtDNA processes or impair their regulation.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Wiley
Copyright: © 2021 International Parkinson and Movement Disorder Society
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