Dataset Information

PROTEOLYTIC ACTIVITIES OF EXTRACELLULAR VESICLES ATTENUATE A-SYNUCLEIN AGGREGATION AND MODULATE ITS TOXICITY

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Synucleinopathy

SUBMITTER: Martina Samiotaki

LAB HEAD: Kostas Vekrellis

PROVIDER: PXD044320 | Pride | 2025-10-06

REPOSITORIES: Pride

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Publications

Proteolytic activities of extracellular vesicles attenuate A-synuclein aggregation.

Vekrellis Kostas K Lamprokostopoulou Agaristi A Melachroinou Katerina K Kokoli Marianna M Zingkou Eleni E Skarveli Marina M Kolianou Asimina A Samiotaki Martina M Sotiropoulou Georgia G

NPJ Parkinson's disease 20250929 1

Extracellular vesicles (EVs) are nano-sized lipid vesicles released into the extracellular space. We investigated the role of mouse brain-derived EVs in α-synuclein (α-syn) degradation and pathology transmission. Using sucrose gradient isolation and biochemical characterization, we found that EVs harbor active proteases that cleave both monomeric α-syn and pre-formed fibrils (PFFs). Protease activity and inhibitor profiling identified cathepsins B and S as key enzymes mediating this cleavage. EV ...[more]

PMID: 41022736

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Project description:Kuznetsov2016(II) - α-syn aggregation kinetics in Parkinson's This theoretical model uses 2-step Finke-Watzky (FW) kinetics todescribe the production, misfolding, aggregation, transport and degradation of α-syn that may lead to Parkinson's Disease (PD). Deregulated α-syn degradation is predicted to be crucialfor PD pathogenesis. This model is described in the article: What can trigger the onset of Parkinson's disease - A modeling study based on a compartmental model of α-synuclein transport and aggregation in neurons. Kuznetsov IA, Kuznetsov AV. Math Biosci 2016 Aug; 278: 22-29 Abstract: The aim of this paper is to develop a minimal model describing events leading to the onset of Parkinson's disease (PD). The model accounts for α-synuclein (α-syn) production in the soma, transport toward the synapse, misfolding, and aggregation. The production and aggregation of polymeric α-syn is simulated using a minimalistic 2-step Finke-Watzky model. We utilized the developed model to analyze what changes in a healthy neuron are likely to lead to the onset of α-syn aggregation. We checked the effects of interruption of α-syn transport toward the synapse, entry of misfolded (infectious) α-syn into the somatic and synaptic compartments, increasing the rate of α-syn synthesis in the soma, and failure of α-syn degradation machinery. Our model suggests that failure of α-syn degradation machinery is probably the most likely cause for the onset of α-syn aggregation leading to PD. This model is hosted on BioModels Database and identified by: BIOMD0000000615. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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