Cells. 2025 Sep 15;14(18):1436. doi: 10.3390/cells14181436.
ABSTRACT
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 α-synuclein (α-Syn) expression, the increased phosphorylation of α-Syn, and Lewy body-like aggregations. Notably, we also observed the increased expression of phosphorylated tau and neurofibrillary tangle-like silver deposits, although amyloid β 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 α-Syn aggregation, which significantly reduced both α-Syn and tau phosphorylation without affecting total α-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.
PMID:41002401 | PMC:PMC12468876 | DOI:10.3390/cells14181436