PXD044320

PXD044320 is an original dataset announced via ProteomeXchange.

Title	PROTEOLYTIC ACTIVITIES OF EXTRACELLULAR VESICLES ATTENUATE A-SYNUCLEIN AGGREGATION AND MODULATE ITS TOXICITY
Description	Extracellular vesicles (EVs) are nano-sized lipid vesicles released from cells into the extracellular milieu. We examined the yet unexplored role(s) of EVs in α-synuclein (α-syn) degradation and recipient-cell homeostasis, and whether EVs can affect the processing of extracellular α-syn species, thereby, their ability to transmit disease pathology. We found that EVs isolated from mouse brain carry active proteolytic enzymes that cleave both the α-syn monomer and pre-formed α-syn fibrils (PFFs) that transmit pathology when injected into mouse brain. We show that EV-mediated proteolysis reduced the ability of α-syn PFFs to seed the aggregation of α-syn monomer, monitored in vitro by thioflavin T assays, and its ability to seed the aggregation of endogenous α-syn in primary neuronal cell cultures. Interestingly, inhibition of the exosomal proteolytic activities by protease inhibitors accelerated the aggregation of α-syn. Proteomic profiling of the exosomal cargo identified a limited number of proteases of different specificities. Protease inhibitor profiling confirmed that exosomal cathepsins B and S are the enzymes responsible for the proteolytic processing of α-syn. We suggest that EVs represent a novel way to regulate the levels of extracellular α-syn and raise the possibility that mis-sorting of cellular proteases to EVs may be a novel post-translational mechanism involved in defective clearance of extracellular α-syn. For the first time, we show that brain EVs, enriched in exosomes possess α-syn degrading activities, and inhibition of these proteolytic activities promotes the aggregation of the protein. Importantly, cleavage of fibrillar α-syn by EV-associated proteases produces species with limited seeding capacity.
HostingRepository	PRIDE
AnnounceDate	2025-10-06
AnnouncementXML	Submission_2025-10-05_16:18:51.640.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Martina Samiotaki
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: NEWT:10090;
ModificationList	monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF-X

Revision	Datetime	Status	ChangeLog Entry
0	2023-08-03 06:57:06	ID requested
⏵ 1	2025-10-05 16:18:52	announced

10.1038/s41531-025-01122-9;

Vekrellis K, Lamprokostopoulou A, Melachroinou K, Kokoli M, Zingkou E, Skarveli M, Kolianou A, Samiotaki M, Sotiropoulou G, Proteolytic activities of extracellular vesicles attenuate A-synuclein aggregation. NPJ Parkinsons Dis, 11(1):277(2025) [pubmed]

submitter keyword: proteomics, a-synuclein,Extracellular vesicles, proteases

Kostas Vekrellis
contact affiliation	Center for Basic Research, Biomedical Research Foundation Academy of Athens, Soranou Efesiou 4, Athens 11527
contact email	vekrellis@bioacademy.gr
lab head
Martina Samiotaki
contact affiliation	Protein Analysis Laboratory B.S.R.C. "Alexander Fleming", Alexander Fleming Street 34 16672, Vari, Greece
contact email	samiotaki@fleming.gr
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/2025/10/PXD044320

PRIDE project URI

• PRIDE
  1. PXD044320
     1. Label: PRIDE project
     2. Name: PROTEOLYTIC ACTIVITIES OF EXTRACELLULAR VESICLES ATTENUATE A-SYNUCLEIN AGGREGATION AND MODULATE ITS TOXICITY