PXD021312 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-09-04 02:50:51 | ID requested | |
⏵ 1 | 2021-09-09 08:21:30 | announced | |
Publication List
Sarkar S, Murphy MA, Dammer EB, Olsen AL, Rangaraju S, Fraenkel E, Feany MB, -synucleinopathy. NPJ Parkinsons Dis, 6(1):40(2020) [pubmed] |
Keyword List
submitter keyword: fly, metabolism, alpha synuclein aggregates, SNCA, Parkinsons Disease |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD021312
- Label: PRIDE project
- Name: Comparative Proteomic Analysis Highlights Metabolic Dysfunction in α-synucleinopathy