7. Project Summary The accumulation of misfolded proteins concurrent with disease progression is a hallmark of degenerative disorders known collectively as proteinopathies. These include dementias such as Alzheimer’s, Parkinson’s and Huntington’s Disease among many others, as well as systemic amyloidosis disorders. However, if and how aggregated species contribute to disease etiology and progression remains poorly understood. Over the past 100 years, there has been significant advancement in understanding the pathological signatures and risk factors of proteinopathies but the molecular mechanisms of disease have remained elusive. In this application, I propose the development of new chemical tools for selectively manipulating aggregate proteostasis in cells and in vivo using a targeted protein degradation approach. To demonstrate feasibility, this approach was previously applied to investigate misfolded tau, leading to new insights into tau as a mediator of cell stress vulnerability in frontotemporal dementia neurons. Several strategies are presented to improve the throughput, scope, and utility of this approach across proteinopathies, as well as future applications. The major innovation of the proposed research is to take technologies and concepts learned from the field of targeted protein degradation (TPD) for cancer therapy, which has been an exceptionally active and successful area of research over the past 5 years, and apply them to central challenges in neurodegenerative diseases, where TPD has yet to be applied broadly. I believe this approach has high potential to yield significant advancement in both our understanding of the molecular mechanisms underlying neurodegenerative diseases and in identifying new therapeutic strategies to treat them.

8. Project Narrative Over 6.4 million Americans are living with a neurodegenerative disorder for which there are no disease-modifying therapies available. The goal of this application is to develop generalizable approaches for the study and treatment of neurodegenerative disorders by discovering new ways to target the misfolded proteins that are a hallmark of this class of diseases with small molecules. If successful, this research will enable scientists to address the long-standing mechanistic disconnect between pathology and phenotype in proteinopathies, and accelerate discovery of therapeutics.