Autophagy enhancement ameliorates tau burden and neurofilament pathology in sporadic PSP-RS neurons

Progressive supranuclear palsy, Richardson's syndrome subtype (PSP-RS), is a tauopathy marked by early axonal pathology and neurodegeneration. Modeling sporadic PSP-RS in human neurons remained a major challenge. Here, we generated midbrain dopaminergic (mDA) neurons from induced pluripotent stem cells (iPSCs) derived from idiopathic PSP-RS patients and healthy controls. Combined transcriptomic and proteomic analysis revealed reduced dopaminergic differentiation and synaptic function, alongside increased phosphorylated and oligomeric Tau, neurofilament accumulation, axonal swelling, and endoplasmic reticulum disorganization. These alterations coincided with impaired autophagic flux and elevated levels of phosphorylated mTOR. Pharmacological inhibition of mTOR restored autophagy and reduced neurofilament and tau pathology. Collectively, our findings implicate mTOR-dependent autophagy dysfunction as a key driver of early axonal pathology of PSP-RS and highlight autophagy modulation as a promising therapeutic avenue. Overall design: RNA-seq profiling of iPSC-derived dopaminergic neurons from pHC and spPSP at DIV60