Cell Cycle Dysfunction and Metabolic Alterations Consistent With Pathological Tau in Progressive Supranuclear Palsy Derived Fibroblasts

Progressive supranuclear palsy (PSP) is a movement neurodegenerative disorder characterized by the primary aggregation of Tau. Although several studies using experimental models of tauopathies have significantly contributed to our understanding of Tau pathology, no animal models currently recapitulate the key cytopathological features of the disease. Primary dermal fibroblasts from 7 PSP patients and 4 healthy donors were collected, and several features were investigated to find promising biological patterns. We found that fibroblasts from PSP patients showed a slower proliferation rate, an increased expression of p16/p21, two cell cycle checkpoints, and an increase in the number of G3BP1-positive stress granules’ association with Tau. Furthermore, we observed an altered mitochondrial homeostasis and a clear differential clustering of their proteome. Our findings suggest that cell cycle dynamics are altered in PSP and highlight, at least in primary fibroblasts, an increase in mitochondrial function, which could be interpreted as a coping strategy for a diseased cell. In line with other studies, these findings reinforce fibroblasts as a suitable platform for investigating neurodegenerative diseases and a reliable patient-derived model for studying PSP pathological features and testing druggable compounds. Furthermore, they pinpoint cell cycle alterations and senescence as a facet that needs extra consideration in PSP.