Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology
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-trans...
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doaj-7c827104395b46819f287f33340f635d2021-02-24T05:49:07ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652021-02-011310.3389/fnagi.2021.591475591475Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease PathologyAnna Wilkaniec0Anna M. Lenkiewicz1Lidia Babiec2Emilia Murawska3Henryk M. Jęśko4Magdalena Cieślik5Carsten Culmsee6Agata Adamczyk7Department of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandDepartment of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandDepartment of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandDepartment of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandDepartment of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandDepartment of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandInstitute of Pharmacology and Clinical Pharmacy, Philipps-University of Marburg, Marburg, GermanyDepartment of Cellular Signalling, Mossakowski Medical Research Centre (PAN), Polish Academy of Sciences, Warsaw, PolandAberrant 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).https://www.frontiersin.org/articles/10.3389/fnagi.2021.591475/fullα-synuclein (α-syn)parkinmitochondria dysfunctionmitophagyPGC-1 alphaParkinson’s disease |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anna Wilkaniec Anna M. Lenkiewicz Lidia Babiec Emilia Murawska Henryk M. Jęśko Magdalena Cieślik Carsten Culmsee Agata Adamczyk |
spellingShingle |
Anna Wilkaniec Anna M. Lenkiewicz Lidia Babiec Emilia Murawska Henryk M. Jęśko Magdalena Cieślik Carsten Culmsee Agata Adamczyk Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology Frontiers in Aging Neuroscience α-synuclein (α-syn) parkin mitochondria dysfunction mitophagy PGC-1 alpha Parkinson’s disease |
author_facet |
Anna Wilkaniec Anna M. Lenkiewicz Lidia Babiec Emilia Murawska Henryk M. Jęśko Magdalena Cieślik Carsten Culmsee Agata Adamczyk |
author_sort |
Anna Wilkaniec |
title |
Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology |
title_short |
Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology |
title_full |
Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology |
title_fullStr |
Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology |
title_full_unstemmed |
Exogenous Alpha-Synuclein Evoked Parkin Downregulation Promotes Mitochondrial Dysfunction in Neuronal Cells. Implications for Parkinson’s Disease Pathology |
title_sort |
exogenous alpha-synuclein evoked parkin downregulation promotes mitochondrial dysfunction in neuronal cells. implications for parkinson’s disease pathology |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Aging Neuroscience |
issn |
1663-4365 |
publishDate |
2021-02-01 |
description |
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). |
topic |
α-synuclein (α-syn) parkin mitochondria dysfunction mitophagy PGC-1 alpha Parkinson’s disease |
url |
https://www.frontiersin.org/articles/10.3389/fnagi.2021.591475/full |
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