Discovery of Noncanonical Autophagy Modulators for Alzheimer's and Related Dementias

About This Grant

ABSTRACT Dementias such as Alzheimer’s disease (AD), frontotemporal degeneration (FTD), and Lewy body dementia (LBD) are progressive neurodegenerative disorders characterized by cognitive decline and pathological protein aggregates, including tau, TDP-43, and α-synuclein. These aggregates result from a breakdown in proteostasis and impairments in macroautophagy, the lysosomal pathway crucial for clearing misfolded proteins and damaged organelles. Enhancing autophagy reduces aggregate accumulation and improves neuronal viability in preclinical models. However, current strategies—such as mTOR inhibition or transcription factor upregulation—are limited by poor specificity, toxicity, or incomplete engagement of the autophagy pathway. To address these limitations, this project will establish two complementary intracellular functional screening platforms designed to discover novel autophagy-activating molecules that restore proteostasis in neuronal models of dementia. These platforms employ genetically encoded libraries capable of engaging dynamic and previously unreached intracellular targets, enabling varied mechanisms of action. In Aim 1, we will discover modulators from a synthetic library using an autophagy flux reporter in neuronal cells. In Aim 2, we will implement a second, orthogonal screening platform based on a distinct peptide scaffold, enabling exploration of complementary chemical and functional spaces. Hits from both approaches will be validated through biochemical and functional assays and tested in human neuronal models to confirm their capacity to promote aggregate clearance. The outcomes will be novel modulators of autophagy and a broadly applicable screening pipeline to advance therapeutic discovery for dementia and other proteinopathy-driven neurodegenerative diseases.