PXD021312

PXD021312 is an original dataset announced via ProteomeXchange.

Title	Comparative Proteomic Analysis Highlights Metabolic Dysfunction in α-synucleinopathy
Description	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 novel pathways and potential 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 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 whole 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.
HostingRepository	PRIDE
AnnounceDate	2021-09-09
AnnouncementXML	Submission_2021-09-09_08:21:29.723.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Dammer
SpeciesList	scientific name: Drosophila melanogaster (Fruit fly); NCBI TaxID: 7227;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-09-04 02:50:51	ID requested
⏵ 1	2021-09-09 08:21:30	announced

Sarkar S, Murphy MA, Dammer EB, Olsen AL, Rangaraju S, Fraenkel E, Feany MB, -synucleinopathy. NPJ Parkinsons Dis, 6(1):40(2020) [pubmed]

submitter keyword: fly, metabolism, alpha synuclein aggregates, SNCA, Parkinsons Disease

Mel B. Feany, M.D. Ph.D
contact affiliation	Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
contact email	mel_feany@hms.harvard.edu
lab head
Eric Dammer
contact affiliation	Emory University
contact email	edammer@emory.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD021312
     1. Label: PRIDE project
     2. Name: Comparative Proteomic Analysis Highlights Metabolic Dysfunction in α-synucleinopathy