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Endogenous alpha-synuclein is essential for the transfer of pathology by exosomes, following PFF inoculation in vivo.

ABSTRACT: Alpha-Synuclein (α-Syn) association with exosomes has been extensively studied both as a physiological process but also as a means of disease transmission under pathological conditions, via an elusive mechanism. Here, we utilized the preformed fibril (PFF) mouse model, as a source of brain-derived exosomes and assessed their pathogenic capacity following intrastriatal injections in host wild type (WT) mouse brain. We further investigated the impact of PFF toxic stimulus in the exosomal cargo independent of the endogenous α-Syn, by isolating exosomes from PFF-injected α-Syn knockout mice. We found that PFF inoculation does not alter the morphology, size distribution, and quantity of brain-derived exosomes, however we show, for the first time, that it triggers changes in the exosomal protein cargo related to synaptic and mitochondrial function, as well as metabolic processes. Importantly, we showed that the presence of the endogenous α-Syn is essential for the exosomes to acquire a pathogenic identity/status, allowing them to mediate disease transmission by inducing phospho-α-Syn pathology, astrogliosis and synaptic alterations in the host mouse brain, thus supporting a role of exosomes in a prion-like mode of infection.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain, Extracellular Exosome

DISEASE(S): Parkinson's Disease

SUBMITTER: Martina Samiotaki

LAB HEAD: Katerina Melachroinou

PROVIDER: PXD036301 | Pride | 2023-08-04

REPOSITORIES: Pride

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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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Endogenous alpha-synuclein is essential for the transfer of pathology by exosomes, following PFF inoculation in vivo.

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