Abstract
Parkinson's disease (PD) is one of the most frequent neurodegenerative disease caused by the preferential, progressive degeneration of the dopaminergic (DA) neurons of the substantia nigra (SN) pars compacta. PD is characterized by a multifaceted pathological process involving protein misfolding, mitochondrial dysfunction, neuroinflammation and metabolism deregulation. The molecular mechanisms governing the complex interplay between the different facets of this process are still unknown. PARK2/Parkin and PARK6/PINK1, two genes responsible for familial forms of PD, act as a ubiquitous core signaling pathway, coupling mitochondrial stress to mitochondrial surveillance, by regulating mitochondrial dynamics, the removal of damaged mitochondrial components by mitochondria-derived vesicles, mitophagy, and mitochondrial biogenesis. Over the last decade, PINK1/Parkin-dependent mitochondrial quality control emerged as a pleiotropic regulatory pathway. Loss of its function impinges on a number of physiological processes suspected to contribute to PD pathogenesis. Its role in the regulation of innate immunity and inflammatory processes stands out, providing compelling support to the contribution of non-cell-autonomous immune mechanisms in PD. In this review, we illustrate the central role of this multifunctional pathway at the crossroads between mitochondrial stress, neuroinflammation and metabolism. We discuss how its dysfunction may contribute to PD pathogenesis and pinpoint major unresolved questions in the field.
Highlights
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders, with more than six million people affected worldwide
Since the discovery of the mitochondrial neurotoxin MPTP in the early 1980s, the idea that mitochondria play a central role in the physiopathology of PD has gained tremendous strength over the last 10 years, through the knowledge acquired on the functions of two proteins involved in autosomal recessive PD forms, PINK1 and Parkin
The body of literature discussed in this review illustrates the multifunctional nature of these proteins, highlighted by their cooperative regulation of a number of aspects related to mitochondrial quality control, of which mitophagy is the most emblematic
Summary
Parkinson’s disease (PD) is one of the most frequent neurodegenerative disorders, with more than six million people affected worldwide. Together with strong emerging links between PINK1 and Parkin and the regulation of pathogen response pathways in C. elegans and mammals (Mira et al, 2004; Manzanillo et al, 2013; Chopra et al, 2014; Kirienko et al, 2015), these observations warrant a detailed analysis of the role of PINK1/Parkin-dependent mitochondrial quality control in cells of the immune system, in the central nervous system, where their dysfunction may contribute to neurodegeneration
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