Mechanistic Insights into Tau Proteostasis: Role of Lipid Dysregulation in Tauopathy & Potential for Targeted Protein Degradation

Abstract

Tauopathies are neurodegenerative diseases characterized by the abnormal accumulation and aggregation of Tau proteins in the brain, leading to neuronal dysfunction and cognitive decline. QC-01-175, a heterobifunctional small molecule degrader, targets aberrant Tau proteins by binding to them with one end and recruiting the E3 ubiquitin ligase Cereblon (CRBN) with the other, promoting their degradation by the proteasome. While QC-01-175 has shown promise in treating tauopathies, its effectiveness in the compromised cellular environments associated with aging—where proteostasis and metabolic functions are impaired—remains uncertain. In this thesis, as a model to examine how QC-01-175 functions under conditions that may impair proteasomal activity, I use cholesterol dysregulation, a metabolic pathway frequently disrupted in neurodegenerative diseases, to better understand the impact of cholesterol metabolic disruptions on Tau aggregation and the therapeutic potential of degraders (Chapter 2). My results demonstrate that cholesterol and its esters accelerate Tau aggregation in a seed-dependent manner, yet QC-01-175 retains its ability to degrade aberrant Tau, even within a cholesterol-compromised environment. These findings highlight the potential of Tau degraders to function effectively in metabolically dysregulated neurons. Additionally, we investigate the native role of CRBN, the E3 ubiquitin ligase recruited by QC-01-175, to understand its biological significance in a neuronal environment (Chapter 3). Proteomic analyses of CRBN knockout neurons show that CRBN is crucial for preventing the accumulation of misfolded proteins, including Tau, and thereby indirectly responsible for maintaining neuronal resilience under cellular stress. Finally, this thesis explores alternative E3 ligases that are preferentially expressed in the central nervous system, which could serve as more effective targets for the next generation of bifunctional degraders (Chapter 4). Collectively, this thesis provides new insights into how cholesterol dysregulation impacts Tau aggregation and how leveraging CRBN with QC-01-175 can mitigate this effect, the native role of CRBN in maintaining Tau proteostasis, and candidate E3 ligases for the development of the next generation of proximity-controlling agents and degrader with improved tissue specificity.