Towards rescuing diverse forms of proteinopathies by induction of autophagic flux

Current treatments for neurodegenerative disorders (proteinopathies) offer limited efficacy and typically target specific genetic forms. The goal of this research project is to discover targets shared across proteinopathies and advance the development of early diagnostic/prognostic tools and disease-modifying pan-proteinopathy approaches.

The team discovered small molecule selective inhibitors of an understudied cellular protein, PIP4K2C, that induce autophagic flux (protein degradation) and extend survival of neurons derived from amyotrophic lateral sclerosis (ALS) patients. This discovery is groundbreaking as autophagic flux impairment is a hallmark of multiple proteinopathies.

The team hypothesizes that PIP4K2C inhibition is an attractive approach for treating multiple proteinopathies by promoting clearance of neurotoxic aggregates.

This project’s goals are to: i) decipher PIP4K2C’s role in ALS pathogenesis and the mechanism by which it suppresses neurotoxin degradation; ii) define the neuroprotective potential of inhibitors targeting PIP4K2C individually or with PIKfyve, a validated ALS target. To achieve these goals, the research team will integrate cutting-edge high-resolution molecular and imaging approaches with functional experiments utilizing unique pharmacological probes and patient-derived neurons.

This bold, interdisciplinary project will provide insight into ALS pathogenesis, validation of a druggable ALS target, and a proof-of-concept for the utility of inducing autophagy as a pan-ALS strategy with implications for other proteinopathies and aging, thereby enhancing brain resilience.