Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy

Abstract The synaptic protein α-synuclein is linked through genetics and neuropathology to the pathogenesis of Parkinson’s disease and related disorders. However, the mechanisms by which α-synuclein influences disease onset and progression are incompletely understood. To identify pathogenic pathways...

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Autores principales:	Souvarish Sarkar, Michael A. Murphy, Eric B. Dammer, Abby L. Olsen, Srikant Rangaraju, Ernest Fraenkel, Mel B. Feany
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/9f38af5472714532a0498ae12dfcd774
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spelling	oai:doaj.org-article:9f38af5472714532a0498ae12dfcd7742021-12-02T15:11:57ZComparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy10.1038/s41531-020-00143-w2373-8057https://doaj.org/article/9f38af5472714532a0498ae12dfcd7742020-12-01T00:00:00Zhttps://doi.org/10.1038/s41531-020-00143-whttps://doaj.org/toc/2373-8057Abstract The synaptic protein α-synuclein is linked through genetics and neuropathology to the pathogenesis of Parkinson’s disease and related disorders. However, the mechanisms by which α-synuclein influences disease onset and progression are incompletely understood. To identify pathogenic pathways and therapeutic targets we performed proteomic analysis in a highly penetrant new Drosophila model of α-synucleinopathy. We identified 476 significantly upregulated and 563 significantly downregulated proteins in heads from α-synucleinopathy model flies compared to controls. We then used multiple complementary analyses to identify and prioritize genes and pathways within the large set of differentially expressed proteins for functional studies. We performed Gene Ontology enrichment analysis, integrated our proteomic changes with human Parkinson’s disease genetic studies, and compared the α-synucleinopathy proteome with that of tauopathy model flies, which are relevant to Alzheimer’s disease and related disorders. These approaches identified GTP cyclohydrolase (GCH1) and folate metabolism as candidate mediators of α-synuclein neurotoxicity. In functional validation studies, we found that the knockdown of Drosophila Gch1 enhanced locomotor deficits in α-synuclein transgenic flies, while folate supplementation protected from α-synuclein toxicity. Our integrative analysis suggested that mitochondrial dysfunction was a common downstream mediator of neurodegeneration. Accordingly, Gch1 knockdown enhanced metabolic dysfunction in α-synuclein transgenic fly brains while folate supplementation partially normalized brain bioenergetics. Here we outline and implement an integrative approach to identify and validate potential therapeutic pathways using comparative proteomics and genetics and capitalizing on the facile genetic and pharmacological tools available in Drosophila.Souvarish SarkarMichael A. MurphyEric B. DammerAbby L. OlsenSrikant RangarajuErnest FraenkelMel B. FeanyNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 6, Iss 1, Pp 1-14 (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 Souvarish Sarkar Michael A. Murphy Eric B. Dammer Abby L. Olsen Srikant Rangaraju Ernest Fraenkel Mel B. Feany Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
description	Abstract The synaptic protein α-synuclein is linked through genetics and neuropathology to the pathogenesis of Parkinson’s disease and related disorders. However, the mechanisms by which α-synuclein influences disease onset and progression are incompletely understood. To identify pathogenic pathways and therapeutic targets we performed proteomic analysis in a highly penetrant new Drosophila model of α-synucleinopathy. We identified 476 significantly upregulated and 563 significantly downregulated proteins in heads from α-synucleinopathy model flies compared to controls. We then used multiple complementary analyses to identify and prioritize genes and pathways within the large set of differentially expressed proteins for functional studies. We performed Gene Ontology enrichment analysis, integrated our proteomic changes with human Parkinson’s disease genetic studies, and compared the α-synucleinopathy proteome with that of tauopathy model flies, which are relevant to Alzheimer’s disease and related disorders. These approaches identified GTP cyclohydrolase (GCH1) and folate metabolism as candidate mediators of α-synuclein neurotoxicity. In functional validation studies, we found that the knockdown of Drosophila Gch1 enhanced locomotor deficits in α-synuclein transgenic flies, while folate supplementation protected from α-synuclein toxicity. Our integrative analysis suggested that mitochondrial dysfunction was a common downstream mediator of neurodegeneration. Accordingly, Gch1 knockdown enhanced metabolic dysfunction in α-synuclein transgenic fly brains while folate supplementation partially normalized brain bioenergetics. Here we outline and implement an integrative approach to identify and validate potential therapeutic pathways using comparative proteomics and genetics and capitalizing on the facile genetic and pharmacological tools available in Drosophila.
format	article
author	Souvarish Sarkar Michael A. Murphy Eric B. Dammer Abby L. Olsen Srikant Rangaraju Ernest Fraenkel Mel B. Feany
author_facet	Souvarish Sarkar Michael A. Murphy Eric B. Dammer Abby L. Olsen Srikant Rangaraju Ernest Fraenkel Mel B. Feany
author_sort	Souvarish Sarkar
title	Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
title_short	Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
title_full	Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
title_fullStr	Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
title_full_unstemmed	Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
title_sort	comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/9f38af5472714532a0498ae12dfcd774
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Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy

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