Paris Mediates Mitochondrial Deficits and Dopaminergic Neuronal Loss In PINK1 and Parkin Linked Parkinson's Disease
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Date
2018-01-16
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Johns Hopkins University
Abstract
Parkinson’s disease (PD) is a common neurodegenerative movement disorder affecting more than five million people worldwide. Afflicted individuals present with an array of debilitating movement symptoms arising from the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While advances have been made in the management of some of the movement symptoms of PD, the etiology of idiopathic Parkinson’s disease remains uncertain. More than two decades after the first rare genetic forms were identified, we still lack clear cut mechanisms to explain the selectivity or toxicity of these mutations, to the detriment of progress on developing disease modifying therapeutics. Nonetheless, genetic modeling of PD still offers our best hope of understanding the pathology of sporadic PD. This is made all the more evident by emerging evidence implicating post-translational modifications of genetic PD linked proteins in pathogenic cascades relevant to both inherited and sporadic disease.
Autosomal-Recessive Parkinson’s disease (AR-PD) is caused by genetic mutations in the E3 ubiquitin ligase parkin or the serine/threonine kinase, PINK1, via a common pathogenic mechanism involving mitochondrial quality control. Moreover, inactivation of parkin through post-translational modification seems to play a broader role in the onset or progression of sporadic PD. Accumulation of the parkin substrate PARIS (Parkin Interacting Substrate, ZNF746) and transcriptional repression of PGC-1 are key mediators of DA neuron death in parkin conditional knockout mice. Correspondingly, PARIS is accumulated in both AR-PD and sporadic PD post-mortem ventral midbrain tissue, and this accumulation is inversely correlated with PGC-1 protein levels.
The impact of PARIS accumulation on cellular mitochondrial pools is unknown. Here we find that parkin loss, leads to PARIS dependent reductions in mitochondrial protein markers and mitochondrial DNA copy number. Using transmission electron microscopy (TEM) we find that there are fewer mitochondria per cell in the ventral midbrain of both parkin conditional knockout mice and virus mediated PARIS overexpressing mice and that more of the mitochondria have structural defects. Using microplate based respirometry, we find that PARIS accumulation in mouse primary ventral midbrain culture leads to PGC-1 dependent reductions in basal oxygen consumption and maximal respiratory capacity.
Additionally, we find that PARIS accumulation and PGC-1 repression mediate DA neuron loss in an adult PINK1 conditional knockdown mouse model. Using in-vitro, cellular and in-vivo analyses we observe that PINK1 phosphorylates PARIS on two conserved serine residues, enhancing its ubiquitination and degradation by parkin. In the absence of PINK1, PARIS accumulates leading to transcriptional repression of PGC-1 and cell death. Taken together these findings implicate PARIS accumulation and PGC-1 repression as nodal events in a pathogenic cascade tethering AR-PD to sporadic disease and leading to impaired mitochondrial biogenesis, declines in mitochondrial mass and deficits in the respiratory capacity of cellular mitochondrial pools in DA neurons.
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Keywords
Parkinson's disease, mitochondria, biogenesis