1. Parkinson's Disease Derived Exosomes Aggravate Neuropathology in SNCA*A53T Mice.
- Author
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Huang Y, Liu Z, Li N, Tian C, Yang H, Huo Y, Li Y, Zhang J, and Yu Z
- Subjects
- Animals, Humans, Mice, alpha-Synuclein genetics, alpha-Synuclein metabolism, Mice, Transgenic, Exosomes metabolism, Exosomes transplantation, MicroRNAs genetics, MicroRNAs metabolism, Parkinson Disease genetics, Parkinson Disease metabolism, Parkinson Disease pathology
- 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-SNCA
A53T 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;92:230-245., (© 2022 American Neurological Association.)- Published
- 2022
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