Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

Abstract Dopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinson’s disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, m...

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Autores principales:	Briana R. De Miranda, Emily M. Rocha, Sandra L. Castro, J. Timothy Greenamyre
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/49863fe210154d65befcb650fa35adf3
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spelling	oai:doaj.org-article:49863fe210154d65befcb650fa35adf32021-12-02T15:11:57ZProtection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM2010.1038/s41531-020-00139-62373-8057https://doaj.org/article/49863fe210154d65befcb650fa35adf32020-12-01T00:00:00Zhttps://doi.org/10.1038/s41531-020-00139-6https://doaj.org/toc/2373-8057Abstract Dopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinson’s disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, many of which are transported through the TOM20–TOM22 outer mitochondrial membrane import receptor machinery. Recent data suggests that post-translational modifications of α-synuclein promote its interaction with TOM20 at the outer mitochondrial membrane and thereby inhibit normal protein import, leading to dysfunction, and death of dopaminergic neurons. As such, preservation of mitochondrial import in the face of α-synuclein accumulation might be a strategy to prevent dopaminergic neurodegeneration, however, this is difficult to assess using current in vivo models of PD. To this end, we established an exogenous co-expression system, utilizing AAV2 vectors to overexpress human α-synuclein and TOM20, individually or together, in the adult Lewis rat substantia nigra to assess whether TOM20 overexpression attenuates α-synuclein-induced dopaminergic neurodegeneration. Twelve weeks after viral injection, we observed that AAV2-TOM20 expression was sufficient to prevent loss of nigral dopaminergic neurons caused by AAV2-αSyn overexpression. The observed TOM20-mediated dopaminergic neuron preservation appeared to be due, in part, to the rescued expression (and presumed import) of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by α-synuclein overexpression. In addition, TOM20 overexpression rescued the expression of the chaperone protein GRP75/mtHSP70/mortalin, a stress-response protein involved in α-synuclein-induced injury. Collectively, these data indicate that TOM20 expression prevents α-synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain.Briana R. De MirandaEmily M. RochaSandra L. CastroJ. Timothy GreenamyreNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 6, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Briana R. De Miranda Emily M. Rocha Sandra L. Castro J. Timothy Greenamyre Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20
description	Abstract Dopaminergic neurons of the substantia nigra are selectively vulnerable to mitochondrial dysfunction, which is hypothesized to be an early and fundamental pathogenic mechanism in Parkinson’s disease (PD). Mitochondrial function depends on the successful import of nuclear-encoded proteins, many of which are transported through the TOM20–TOM22 outer mitochondrial membrane import receptor machinery. Recent data suggests that post-translational modifications of α-synuclein promote its interaction with TOM20 at the outer mitochondrial membrane and thereby inhibit normal protein import, leading to dysfunction, and death of dopaminergic neurons. As such, preservation of mitochondrial import in the face of α-synuclein accumulation might be a strategy to prevent dopaminergic neurodegeneration, however, this is difficult to assess using current in vivo models of PD. To this end, we established an exogenous co-expression system, utilizing AAV2 vectors to overexpress human α-synuclein and TOM20, individually or together, in the adult Lewis rat substantia nigra to assess whether TOM20 overexpression attenuates α-synuclein-induced dopaminergic neurodegeneration. Twelve weeks after viral injection, we observed that AAV2-TOM20 expression was sufficient to prevent loss of nigral dopaminergic neurons caused by AAV2-αSyn overexpression. The observed TOM20-mediated dopaminergic neuron preservation appeared to be due, in part, to the rescued expression (and presumed import) of nuclear-encoded mitochondrial electron transport chain proteins that were inhibited by α-synuclein overexpression. In addition, TOM20 overexpression rescued the expression of the chaperone protein GRP75/mtHSP70/mortalin, a stress-response protein involved in α-synuclein-induced injury. Collectively, these data indicate that TOM20 expression prevents α-synuclein-induced mitochondrial dysfunction, which is sufficient to rescue dopaminergic neurons in the adult rat brain.
format	article
author	Briana R. De Miranda Emily M. Rocha Sandra L. Castro J. Timothy Greenamyre
author_facet	Briana R. De Miranda Emily M. Rocha Sandra L. Castro J. Timothy Greenamyre
author_sort	Briana R. De Miranda
title	Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20
title_short	Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20
title_full	Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20
title_fullStr	Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20
title_full_unstemmed	Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20
title_sort	protection from α-synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor tom20
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/49863fe210154d65befcb650fa35adf3
work_keys_str_mv	AT brianardemiranda protectionfromasynucleininduceddopaminergicneurodegenerationbyoverexpressionofthemitochondrialimportreceptortom20 AT emilymrocha protectionfromasynucleininduceddopaminergicneurodegenerationbyoverexpressionofthemitochondrialimportreceptortom20 AT sandralcastro protectionfromasynucleininduceddopaminergicneurodegenerationbyoverexpressionofthemitochondrialimportreceptortom20 AT jtimothygreenamyre protectionfromasynucleininduceddopaminergicneurodegenerationbyoverexpressionofthemitochondrialimportreceptortom20
_version_	1718387625970106368

Protection from α-Synuclein induced dopaminergic neurodegeneration by overexpression of the mitochondrial import receptor TOM20

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