Induced Pluripotent Stem Cell-Derived Dopaminergic Neurons From Familial Parkinson'S Disease Patients Display Alpha-Synuclein Pathology And Abnormal Mitochondrial Morphology

Accumulation of alpha-synuclein (alpha-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson's disease (PD), which are associated with the loss of dopaminergic neurons. Although alpha-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and alpha-syn gene (SNCA) triplication display pathological alpha-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological alpha-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.