Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein
Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship betwee...
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doaj-7dfa04f473804946a578917f019e470a2021-02-14T12:29:30ZengBMCActa Neuropathologica Communications2051-59602020-02-018111610.1186/s40478-020-0894-0Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synucleinChris McKinnon0Mitchell L. De Snoo1Elise Gondard2Clemens Neudorfer3Hien Chau4Sophie G. Ngana5Darren M. O’Hara6Jonathan M. Brotchie7James B. Koprich8Andres M. Lozano9Lorraine V. Kalia10Suneil K. Kalia11Krembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkKrembil Research Institute, Toronto Western Hospital, University Health NetworkAbstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein UbG76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo.https://doi.org/10.1186/s40478-020-0894-0Parkinson’s diseaseUbiquitin-proteasome systemα-SynucleinNeurodegeneration |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chris McKinnon Mitchell L. De Snoo Elise Gondard Clemens Neudorfer Hien Chau Sophie G. Ngana Darren M. O’Hara Jonathan M. Brotchie James B. Koprich Andres M. Lozano Lorraine V. Kalia Suneil K. Kalia |
spellingShingle |
Chris McKinnon Mitchell L. De Snoo Elise Gondard Clemens Neudorfer Hien Chau Sophie G. Ngana Darren M. O’Hara Jonathan M. Brotchie James B. Koprich Andres M. Lozano Lorraine V. Kalia Suneil K. Kalia Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein Acta Neuropathologica Communications Parkinson’s disease Ubiquitin-proteasome system α-Synuclein Neurodegeneration |
author_facet |
Chris McKinnon Mitchell L. De Snoo Elise Gondard Clemens Neudorfer Hien Chau Sophie G. Ngana Darren M. O’Hara Jonathan M. Brotchie James B. Koprich Andres M. Lozano Lorraine V. Kalia Suneil K. Kalia |
author_sort |
Chris McKinnon |
title |
Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein |
title_short |
Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein |
title_full |
Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein |
title_fullStr |
Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein |
title_full_unstemmed |
Early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein |
title_sort |
early-onset impairment of the ubiquitin-proteasome system in dopaminergic neurons caused by α-synuclein |
publisher |
BMC |
series |
Acta Neuropathologica Communications |
issn |
2051-5960 |
publishDate |
2020-02-01 |
description |
Abstract Parkinson’s disease is a progressive neurodegenerative disorder characterised by the accumulation of misfolded α-synuclein in selected brain regions, including the substantia nigra pars compacta (SNpc), where marked loss of dopaminergic neurons is also observed. Yet, the relationship between misfolded α-synuclein and neurotoxicity currently remains unclear. As the principal route for degradation of misfolded proteins in mammalian cells, the ubiquitin-proteasome system (UPS) is critical for maintenance of cellular proteostasis. Misfolded α-synuclein impairs UPS function and contributes to neuronal death in vitro. Here, we examine its effects in vivo using adeno-associated viruses to co-express A53T α-synuclein and the ubiquitinated reporter protein UbG76V-GFP in rat SNpc. We found that α-synuclein over-expression leads to early-onset catalytic impairment of the 26S proteasome with associated UPS dysfunction, preceding the onset of behavioural deficits and dopaminergic neurodegeneration. UPS failure in dopaminergic neurons was also associated with selective accumulation of α-synuclein phosphorylated at the serine 129 residue, which has previously been linked to increased neurotoxicity. Our study highlights a role for α-synuclein in disturbing proteostasis which may contribute to neurodegeneration in vivo. |
topic |
Parkinson’s disease Ubiquitin-proteasome system α-Synuclein Neurodegeneration |
url |
https://doi.org/10.1186/s40478-020-0894-0 |
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