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Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology

Authors
  • Wilkaniec, Anna1
  • Lenkiewicz, Anna M.1
  • Babiec, Lidia1
  • Murawska, Emilia1
  • Jęśko, Henryk M.1
  • Cieślik, Magdalena1
  • Culmsee, Carsten2
  • Adamczyk, Agata1
  • 1 Department of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw , (Poland)
  • 2 Institute of Pharmacology and Clinical Pharmacy, Philipps-University of Marburg, Marburg , (Germany)
Type
Published Article
Journal
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Publication Date
Feb 24, 2021
Volume
13
Identifiers
DOI: 10.3389/fnagi.2021.591475
PMCID: PMC7943853
Source
PubMed Central
Keywords
License
Unknown

Abstract

Aberrant secretion and accumulation of α-synuclein (α-Syn) as well as the loss of parkin function are associated with the pathogenesis of Parkinson’s disease (PD). Our previous study suggested a functional interaction between those two proteins, showing that the extracellular α-Syn evoked post-translational modifications of parkin, leading to its autoubiquitination and degradation. While parkin plays an important role in mitochondrial biogenesis and turnover, including mitochondrial fission/fusion as well as mitophagy, the involvement of parkin deregulation in α-Syn-induced mitochondrial damage is largely unknown. In the present study, we demonstrated that treatment with exogenous α-Syn triggers mitochondrial dysfunction, reflected by the depolarization of the mitochondrial membrane, elevated synthesis of the mitochondrial superoxide anion, and a decrease in cellular ATP level. At the same time, we observed a protective effect of parkin overexpression on α-Syn-induced mitochondrial dysfunction. α-Syn-dependent disturbances of mitophagy were also shown to be directly related to reduced parkin levels in mitochondria and decreased ubiquitination of mitochondrial proteins. Also, α-Syn impaired mitochondrial biosynthesis due to the parkin-dependent reduction of PGC-1α protein levels. Finally, loss of parkin function as a result of α-Syn treatment induced an overall breakdown of mitochondrial homeostasis that led to the accumulation of abnormal mitochondria. These findings may thus provide the first compelling evidence for the direct association of α-Syn-mediated parkin depletion to impaired mitochondrial function in PD. We suggest that improvement of parkin function may serve as a novel therapeutic strategy to prevent mitochondrial impairment and neurodegeneration in PD (thereby slowing the progression of the disease).

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