PXD040141-1

PXD040141 is an original dataset announced via ProteomeXchange.

Title	Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease
Description	Auxilin 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.
HostingRepository	PRIDE
AnnounceDate	2023-02-16
AnnouncementXML	Submission_2023-02-16_08:23:42.265.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	TuKietLam
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-16 03:45:16	ID requested
⏵ 1	2023-02-16 08:23:42	announced

Dataset with its publication pending

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

TuKietLam
contact affiliation	Keck MS & Proteomics Resource Yale School of Medicine
contact email	tukiet.lam@yale.edu
lab head
TuKietLam
contact affiliation	Yale University
contact email	tukiet.lam@yale.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/02/PXD040141

PRIDE project URI

• PRIDE
  1. PXD040141
     1. Label: PRIDE project
     2. Name: Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease