Modeling Synucleinopathy Using hESC-Derived Cerebral Organoids

초록

Animal and cellular models harboring SNCA gene mutations have been instrumental in synucleinopathy, but faithful human brain models remain limited. Here, we report the development of a human cerebral organoid (CO) model of synucleinopathy carrying the Ala53Thr mutation in SNCA (SNCAA53T). Using a human embryonic stem cell (hESC) line overexpressing SNCAA53T (A53T hESC line), we generated COs (A53T COs) that recapitulate hallmark features of synucleinopathy. These A53T COs exhibited elevated alpha-synuclein (alpha-Syn) expression, the increased phosphorylation of alpha-Syn, and Lewy body-like aggregations. Notably, we also observed the increased expression of phosphorylated tau and neurofibrillary tangle-like silver deposits, although amyloid beta expression and accumulation remained unchanged. To evaluate the utility of this model in drug screening, we treated A53T COs with synuclean D (SynD), an inhibitor of alpha-Syn aggregation, which significantly reduced both alpha-Syn and tau phosphorylation without affecting total alpha-Syn levels. Together, our findings establish a robust hESC-derived synucleinopathy CO model harboring the SNCAA53T mutation, demonstrating its potential as a valuable tool for therapeutic drug screening.

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