51. Modeling Lewy body disease with SNCA triplication iPSC-derived cortical organoids and identifying therapeutic drugs.
- Author
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Jin Y, Li F, Li Z, Ikezu TC, O'Leary J, Selvaraj M, Zhu Y, Martens YA, Koga S, Santhakumar H, Li Y, Lu W, You Y, Lolo K, DeTure M, Beasley AI, Davis MD, McLean PJ, Ross OA, Kanekiyo T, Ikezu T, Caulfield T, Carr J, Wszolek ZK, Bu G, Dickson DW, and Zhao N
- Subjects
- Humans, Mitochondria metabolism, Mitochondria drug effects, Mitochondria genetics, Neurons metabolism, Neurons drug effects, Neurons pathology, Cerebral Cortex metabolism, Cerebral Cortex pathology, Cerebral Cortex drug effects, Drug Evaluation, Preclinical, alpha-Synuclein metabolism, alpha-Synuclein genetics, Organoids metabolism, Organoids drug effects, Organoids pathology, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells drug effects, Induced Pluripotent Stem Cells cytology, Lewy Body Disease pathology, Lewy Body Disease genetics, Lewy Body Disease metabolism, Lewy Body Disease drug therapy
- 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 Administration-approved drugs and identified four candidates (entacapone, tolcapone, phenazopyridine hydrochloride, and zalcitabine) that inhibited α-SYN seeding activity in real-time quaking-induced conversion assays with human brains, reduced α-SYN aggregation, and alleviated mitochondrial dysfunction in SNCA triplication organoids and excitatory neurons. Our findings establish human cortical LBD models and suggest potential therapeutic drugs targeting α-SYN aggregation for LBD.
- Published
- 2024
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