DISTINCT TAU ISOFORMS DIFFERENTIALLY DISRUPT AUTOPHAGY AND MITOCHONDRIAL FUNCTION: IMPLICATIONS FOR TAUOPATHIES

Tauopathies comprise a heterogeneous group of neurodegenerative disorders characterized by intraneuronal accumulation of tau protein. Different tauopathies subtypes are defined by the predominant tau isoform accumulated, either 3-repeat (3R) tau, as in Pick’s disease, or 4-repeat (4R) tau, as in progressive supranuclear palsy and corticobasal degeneration. While tau accumulation is a central feature of these diseases, whether distinct tau isoforms trigger neurodegeneration through shared or isoform-specific mechanisms remains unclear. In this study, we investigated the impact of 3R and 4R tau accumulation on autophagy flux, mitochondrial homeostasis, and neuronal survival. We employed disease-in-a-dish models of tauopathies, including SH-SY5Y cells, induced pluripotent stem cell–derived neurons, and human brain organoids. Tau accumulation induced dysfunction of both autophagy and mitochondrial pathways in an isoform-dependent manner. Impaired autophagy flux was observed selectively in models accumulating 4R tau, whereas mitochondrial homeostasis was disrupted by both 3R and 4R tau isoforms. Interestingly, while tau accumulation resulted in neurotoxicity across all models, with significantly different neuronal death rates between 3R and 4R tau conditions were found. These findings indicate that distinct tau isoforms engage specific molecular pathways affecting cellular homeostasis and neuronal viability. Our results provide mechanistic insight into the clinical tauopathies heterogeneity and support the development of tau isoform-specific therapeutic strategies targeting key pathogenic processes.