Modeling Lewy body disease with <i>SNCA</i> triplication iPSC-derived cortical organoids and identifying therapeutic drugs.

ABSTRACT: Aggregated α-synuclein (α-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying α-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we recapitulated α-SYN pathologies in human induced pluripotent stem cells (iPSCs)-derived cortical organoids generated from patients with LBD with SNCA gene triplication. Single-cell RNA sequencing, combined with functional and molecular validation, identified synaptic and mitochondrial dysfunction in excitatory neurons exhibiting high expression of the SNCA gene, aligning with observations in the cortex of autopsy-confirmed LBD human brains. Furthermore, we screened 1280 Food and Drug Admi

SUBMITTER: Jin Y 

PROVIDER: S-EPMC11389790 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature