Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of alpha-synuclein (alpha-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDAN5), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of alpha-Syn aggregation for the preferential loss of mDAN5 in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the alpha-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDAN5 and cortical projection neurons (CPN5). SNCA dosage increase did not influence the differentiation efficiency of mDAN5 and CPN5. However, elevated alpha-Syn pathology, as revealed by enhanced alpha-Syn insolubility and phosphorylation, was determined in PD-derived mDAN5 compared with PD CPN5. PD-derived mDAN5 exhibited higher levels of reactive oxygen species and protein nitration levels compared with CPN5, which might underlie elevated alpha-Syn pathology observed in mDAN5. Finally, increased neuronal death was observed in PD-derived mDAN5 compared to PD CPN5 and to control mDAN5 and CPN5. Our results reveal, for the first time, a higher alpha-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDAN5 compared with PD CPN5 from the same patient. The finding implies the contribution of pathogenic alpha-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.