Mitochondrial deficits and activation of autophagy in human iPSC-derived midbrain dopaminergic progenitors from patients with Wilson’s disease

Wilson's disease (WD) is a disorder of copper metabolism that can cause severe neurological manifestations, including parkinsonism. This suggests that nigrostriatal dopaminergic system dysfunction may contribute to neurological WD. However, pathological changes in the central nervous system associated with WD remain poorly understood due to limited patient samples and the absence of animal models with robust neurological phenotypes. In our previous research, we established an induced pluripotent stem cell (iPSC) line from a WD patient carrying the R778L mutation. Here, we successfully differentiated iPSCs from both WD patients and healthy controls into midbrain dopaminergic progenitor cells (WD-mDAPCs and HC-mDAPCs, respectively). WD-mDAPCs exhibited cell-type-specific mitochondrial vulnerability, indicating that mitochondrial dysfunction may play an important role in WD neuropathogenesis. Furthermore, an increased number of autophagosomes was detected in WD-mDAPCs. Thus, we have established a novel cellular model for investigating neural abnormalities in WD. Therapeutic strategies targeting mitochondrial protection and autophagy activation may alleviate copper-induced neurological impairment in WD.