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PXD040141

PXD040141 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease
DescriptionAuxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin-knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dys-homeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.
HostingRepositoryPRIDE
AnnounceDate2023-02-16
AnnouncementXMLSubmission_2023-02-16_08:23:42.265.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterTuKietLam
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListmonohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
InstrumentQ Exactive Plus
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-02-16 03:45:16ID requested
12023-02-16 08:23:42announced
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: Dorsal striatum, Substantia nigra, Endolysosomal system, Dopamine, α-Synuclein, Clathrin coated vesicles, Synaptic autophagy,Clathrin mediated endocytosis, Axonal deformity, Lewy bodies, L-DOPA
Contact List
TuKietLam
contact affiliationKeck MS & Proteomics Resource Yale School of Medicine
contact emailtukiet.lam@yale.edu
lab head
TuKietLam
contact affiliationYale University
contact emailtukiet.lam@yale.edu
dataset submitter
Full Dataset Link List
Dataset FTP location
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PRIDE project URI
Repository Record List
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