Fig. 5

Graphical abstract of the study. Human midbrain dopaminergic (DA) neurons (mDANs) from patients with a monoallelic SNCA locus duplication were differentiated from induced pluripotent stem cells (iPSC) and neuronal precursor cells (NPCs). Increased aggregated αSyn conformer levels, including toxic oligomeric αSyn conformers (oligomeric α-Synuclein), increased signals of reactive oxygen species (ROS) probes in both cytoplasm and mitochondria (Mito.), mitochondrial dysfunction (measured by relative ATP levels), and increased caspase-3 activation in neurons (reflecting early neuronal cell death) were determined in human iPSC-derived mDANs from patients with a monoallelic SNCA locus duplication, recapitulating neuropathological hallmarks of PD. Treatment of mDANs with the αSyn misfolding inhibitor NPT100-18A, ameliorating αSyn aggregation, specifically reduces mitochondrial ROS probe levels and rescues caspase-3 activation in patient-derived neurons, thereby revealing the efficacy of the misfolding inhibitor in limiting loss of mDANs in PD