Single nucleus RNA sequencing data of Lewy Body Dementia (LBD) brains
Aggregated a-synuclein (a-SYN) proteins, encoded by the SNCA gene, are hallmarks of Lewy body disease (LBD), affecting multiple brain regions. However, the specific mechanisms underlying a-SYN pathology in cortical neurons, crucial for LBD-associated dementia, remain unclear. Here, we generated human cortical LBD models by differentiating induced pluripotent stem cells (iPSCs) from SNCA triplication LBD patients into cerebral organoids and observed increased levels of pathological a-SYN in these organoids. Single-cell RNA sequencing revealed prominent expression of the SNCA gene in excitatory neurons, which exhibited synaptic and mitochondrial dysfunction, consistent with findings in the cortex of LBD human brains. Furthermore, screening 1280 FDA-approved drugs identified four candidates, which inhibited a-SYN seeding in RT-QuIC assay, reduced a-SYN aggregation and alleviated mitochondrial dysfunction in SNCA triplication iPSC models. Our findings provide valuable insights into the development of cortical LBD models and the discovery of potential drugs targeting a-SYN aggregation. Overall design: Single nucleus RNA sequencing of isolated nuclei from superior cortext region of LBD patients including SNCA duplication and SNCA triplication carriers and healthy individuals. Three brains from control individuals and five brains from LBD patients including one SNCA duplication and one SNCA triplication carrier were used.