PXD038362

PXD038362 is an original dataset announced via ProteomeXchange.

Title	The role of damaged mitochondrial DNA in Parkinson Disease
Description	Parkinson disease (PD) is a neurodegenerative disease believed to initiate in the brainstem and then spread throughout the brain. The mechanism by which this occurs is not yet fully understood, but here we show that damaged mitochondrial DNA (mtDNA) plays an important role in this process, which can be initiated by dysregulation of the IFNb/IFNAR signalling pathway. We report that lack of neuronal IFNb/IFNAR, which is associated to the development of PD, causes oxidization, mutation, and deletion in mtDNA. Damaged mtDNA is subsequently extruded extracellularly and can induce PD symptoms like motor and cognitive impairments in healthy mouse brains. It even leads to neurodegeneration in brain regions far from the injection site, suggesting that damaged mtDNA triggers the propagation of PD hallmarks through the brain. We further show that the mechanism by which damaged mtDNA causes pathology in healthy neurons is independent of cGAS and IFNb/IFNAR, but it is mediated by activation of dual Toll-like receptor (TLR)4/9 pathways. Through a proteomic analysis of extracellular vesicles containing the damaged mtDNA, we identified the TLR4 activator Ribosomal Protein S3 (Rps3) and established that Rps3 is a key effector protein involved in damaged mtDNA extrusion and recognition. Collectively, these results reveal a new molecular pathway by which damaged mtDNA can initiate and propagate Parkinson's Disease, paving the way for potential new therapies or disease monitoring.
HostingRepository	PRIDE
AnnounceDate	2023-09-18
AnnouncementXML	Submission_2023-09-18_01:39:14.018.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	ErwinSchoof
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-25 02:15:53	ID requested
⏵ 1	2023-09-18 01:39:14	announced

Dataset with its publication pending

submitter keyword: brain, LC-MS, extracellular vesicles,human

ShohrehIssazadeh-Navikas
contact affiliation	Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
contact email	shohreh.issazadeh@bric.ku.dk
lab head
ErwinSchoof
contact affiliation	Technical University of Denmark
contact email	erws@dtu.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038362
     1. Label: PRIDE project
     2. Name: The role of damaged mitochondrial DNA in Parkinson Disease