Characterizing and targeting autophagy initiation via ULK1 in a tauopathy context

Abstract

Tauopathies are neurodegenerative diseases defined by the accumulation of pathological tau protein and currently lack effective disease-modifying therapies. Autophagy is an endogenous cellular pathway capable of clearing aggregation-prone proteins, but its broad pharmacological activation is limited by off-target effects. This dissertation investigates whether selective activation of autophagy initiation through Unc-51 like kinase 1 (ULK1) can promote tau clearance in human-relevant models of tauopathy. Postmortem brain tissue from individuals with tauopathy and controls was analyzed to assess endogenous autophagy markers, revealing disrupted autophagic regulation correlated with tau burden and implicating impaired ULK1 signaling. Guided by these observations, patient-derived induced pluripotent stem cell (iPSC) neurons and three-dimensional brain organoids harboring pathogenic tau mutations were treated with small-molecule ULK1 activators. Direct activation of ULK1 robustly induced autophagic flux and reduced total and phosphorylated tau across multiple genetic contexts without overt toxicity. Mechanistic studies further indicated that ULK1 activation acts independently of autophagy initiation complex assembly. Lastly, tool development for future study into the intersection of tau and autophagy contributes to future work in this field. Together, these findings establish ULK1-mediated autophagy initiation as a dysregulated but therapeutically tractable pathway in tauopathy and support targeted autophagy activation as a promising strategy for tau clearance.