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Comparative proteomic analysis highlights metabolic dysfunction in α-synucleinopathy
Name
s41531-020-00143-w.pdf
Description
Published version
Size
2.43 MB
Format
Adobe PDF
Checksum (MD5)
db6715fcfdcd556f9e4146265e24557c
Author(s)
Sarkar, Souvarish
Murphy, Michael A
Dammer, Eric B
Olsen, Abby L
Rangaraju, Srikant
Fraenkel, Ernest
Feany, Mel B
Date Issued
2020
Journal
npj Parkinson's Disease
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 2020, The Author(s). 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.
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1038/S41531-020-00143-W
