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Endogenous Alpha-Synuclein is Essential for the Transfer of Pathology by Exosome-Enriched Extracellular Vesicles, Following Inoculation with Preformed Fibrils in vivo.

ABSTRACT: The main pathological hallmark of Parkinson's disease (PD) and related synucleinopathies is the presence of intracellular proteinaceous aggregates, enriched in the presynaptic protein alpha-Synuclein (α-Syn). α-Syn association with exosomes has been previously documented both as a physiological process of secretion and as a pathological process of disease transmission, however, critical information about the mechanisms governing this interplay is still lacking. To address this, we utilized the α-Syn preformed fibril (PFF) mouse model of PD, as a source of brain-derived exosome-enriched extracellular vesicles (ExE-EVs) and assessed their pathogenic capacity following intrastriatal injections in host wild type (WT) mouse brain. We further investigated the impact of the fibrillar α-Syn on the exosomal cargo independent of the endogenous α-Syn, by isolating ExE-EVs from PFF-injected α-Syn knockout mice. Although PFF inoculation does not alter the morphology, size distribution, and quantity of brain-derived ExE-EVs, it triggers changes in the exosomal proteome 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 ExE-EVs to acquire a pathogenic capacity, allowing them to mediate disease transmission by inducing phosphorylated-α-Syn pathology. Notably, misfolded α-Syn containing ExE-EVs when injected in WT mice were able to induce astrogliosis and synaptic alterations in the host brain, at very early stages of α-Syn pathology, preceding the formation of the insoluble α-Syn accumulations. Collectively, our data suggest that exosomal cargo defines their ability to spread α-Syn pathology.

SUBMITTER: Melachroinou K

PROVIDER: S-EPMC10917543 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Endogenous Alpha-Synuclein is Essential for the Transfer of Pathology by Exosome-Enriched Extracellular Vesicles, Following Inoculation with Preformed Fibrils in vivo.

Melachroinou Katerina K Divolis Georgios G Tsafaras George G Karampetsou Mantia M Fortis Sotirios S Stratoulias Yannis Y Papadopoulou Gina G Kriebardis Anastasios G AG Samiotaki Martina M Vekrellis Kostas K

Aging and disease 20240401 2

The main pathological hallmark of Parkinson's disease (PD) and related synucleinopathies is the presence of intracellular proteinaceous aggregates, enriched in the presynaptic protein alpha-Synuclein (α-Syn). α-Syn association with exosomes has been previously documented both as a physiological process of secretion and as a pathological process of disease transmission, however, critical information about the mechanisms governing this interplay is still lacking. To address this, we utilized the α ...[more]

PMID: 37548944

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Project description:Synucleinopathies are characterized by the accumulation of insoluble ?-synuclein (?Syn). To test whether ?Syn aggregates modulate synaptic activity, we used a recently developed model in primary neurons for inducing ?Syn pathology. We demonstrated that preformed fibrils (PFFs) generated with recombinant human ?Syn compromised synaptic activity in a time- and dose-dependent manner and that the magnitude of these deficits correlated with the formation of ?Syn pathology in cultured excitatory hippocampal neurons from both sexes of mice. Remarkably, acute passive infusion of ?Syn PFFs from whole-cell patch-clamp pipette decreased mEPSC frequency within 10 min followed by induction of ?Syn pathology within 1 d. Moreover, by direct addition of ?Syn PFFs into culture medium, the formation of misfolded ?Syn inclusions dramatically compromised the colocalization of synaptic markers and altered dynamic changes of dendritic spines, but the viability of neurons was not affected up to 7 d post-treatment with ?Syn PFFs. Our data indicate that intraneuronal ?Syn fibrils impaired the initiation of synaptogenesis and their physiological functions, thereby suggesting that targeting synaptic dysfunction in synucleinopathies may provide a promising therapeutic direction.SIGNIFICANCE STATEMENT Under pathological conditions, the presynaptic protein ?-synuclein (?Syn) aggregates to form intraneuronal inclusions. To understand how and to what extent ?Syn aggregates modulate synaptic activity before neuron loss, we demonstrate that ?Syn preformed fibrils (PFFs) reduced synaptic activity in a dose- and time-dependent manner. The magnitude of these deficits correlated with the deposition of ?Syn pathology, which dramatically compromised the colocalization of synaptic markers and altered the dendritic spine dynamics. The present work further highlights the impact of ?Syn PFFs on synaptogenesis and physiological function, which may be applicable to other types of synucleinopathies.

Dataset Information

Endogenous Alpha-Synuclein is Essential for the Transfer of Pathology by Exosome-Enriched Extracellular Vesicles, Following Inoculation with Preformed Fibrils in vivo.

Publications

Endogenous Alpha-Synuclein is Essential for the Transfer of Pathology by Exosome-Enriched Extracellular Vesicles, Following Inoculation with Preformed Fibrils in vivo.

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