Parkinson's Disease Derived Exosomes Aggravate Neuropathology in SNCA*A53T Mice.

ABSTRACT

OBJECTIVE: Accumulation of α-synuclein (α-syn) in neurons is a prominent feature of Parkinson's disease (PD). Recently, researchers have considered that extracellular vesicles (EVs) may play an important role in protein exportation and propagation, and α-syn-containing EVs derived from the central nervous system (CNS) have been detected in peripheral blood. However, mechanistic insights into CNS-derived EVs have not been well-described. METHODS: Likely neurogenic EVs were purified from the plasma of PD patients and healthy controls using a well-established immunoprecipitation assay with anti-L1CAM-coated beads. A Prnp-SNCAA53T transgenic PD mouse model was used to evaluate the neuronal pathology induced by PD-derived L1CAM-purified EVs. EV-associated microRNA (miRNA) profiling was used to screen for altered miRNAs in PD-derived L1CAM-purified EVs. RESULTS: PD patient-derived L1CAM-purified (likely neurogenic) EVs facilitated α-syn pathology and neuron loss in Prnp-SNCAA53T transgenic PD mice. The miRNA, novel_miR_44438, was significantly increased in the PD group, which promoted α-syn accumulation and neuronal degeneration in a dose-dependent manner. Novel _miR_44438 directly targets NDST1 mRNA and inhibits the function of heparan sulfate, thus preventing exosome biogenesis and α-syn release from exosomes. INTERPRETATION: Novel_miR_44438 in PD-derived L1CAM-purified EVs inhibits the α-syn efflux from neurons thereby promoting the pathological accumulation and aggregation of α-syn. ANN NEUROL 2022;92230-245.