Patient-derived fibroblasts as a model for Progressive Supranuclear Palsy: Recapitulating disease associated alteration in autophagy, tau, and mitochondrial function

Progressive supranuclear palsy (PSP) is a primary tauopathy within a group of neurodegenerative disorders, characterized by pathological tau aggregation in the brain. SQSTM1/P62, a key autophagy marker, delivers ubiquitinated proteins to the autophagosome, regulating tau degradation. Here, we studied skin-derived fibroblasts from a PSP patient carrying a genetic SQSTM1/P62 p.Pro392Leu variant to determine whether autophagic flux and tau metabolism are altered. Tau, p-tau, SQSTM1/P62, and LC3 levels were analyzed by Western blot in fibroblasts from the patient and two control subjects to assess autophagy alterations and potential defects in tau degradation. Patient-derived fibroblasts showed altered autophagic flux, with increased LC3II and p62 after starvation treatment together with increased tau and phospho-tau levels. Mitochondrial morphology (MitoTracker) and membrane potential (TMRE) confocal analysis revealed increased mitochondrial fragmentation and membrane depolarization, indicating disrupted mitochondrial homeostasis. Interestingly, mitochondria-lysosome association assessed by confocal microscopy and colocalization analysis revealed altered mitophagy in patient-derived fibroblasts. Together, these results indicate that both autophagy and mitophagy are specifically impaired in fibroblasts carrying P62 Pro392Leu variant, and that tau is abnormally processed in this cellular model, suggesting that autophagy impairments may contribute to disease pathogenesis.