Deciphering ubiquilin-mediated proteostasis mechanisms in alzheimer's disease and related dementias defects in protein homeostasis are a hallmark of alzheimer's disease and related dementias (ADRDS)

The National Institute on Aging awarded the University of Pittsburgh $673,702 on September 1, 2026, under the Aging Research program (CFDA 93.866) to support research deciphering ubiquilin-mediated proteostasis mechanisms in Alzheimer's disease and related dementias.

The research addresses knowledge gaps in ubiquilin function and protein homeostasis defects underlying neurodegenerative disease. The project will elucidate how STI1 domain binding and E3 ligase recruitment affect cellular fitness and ADRD protein stability, phase separation, and function through a combination of structure/function studies and neuronal cell biology techniques. Preliminary data include the first crystal structure of the STI1 domain bound to a substrate, in vitro assays linking ubiquitination and phase separation to substrate protection from degradation, and cellular data demonstrating that ubiquilin protects substrates from proteasomal degradation in correlation with E3 ligase recruitment and condensate formation.

Work is performed at the University of Pittsburgh in Pittsburgh, Pennsylvania, with a period of performance extending from September 1, 2026, through May 31, 2031. The award is classified as a Project Grant, a standard assistance type for investigator-initiated biomedical research under the National Institute on Aging's mission to support research on preventing and treating Alzheimer's disease and related dementias.

Ubiquilins are a family of proteins at the nexus of cellular proteostasis and have emerged as key players in the pathogenesis of these neurodegenerative disorders. Despite their clear clinical relevance, many aspects of ubiquilin function remain unclear, such as: how point mutations in the STI1 domain lead to neurodegenerative disease, the role of phase separation in ubiquilin function, or why ubiquilins, which are normally described as proteasomal shuttle factors, paradoxically stabilize some substrates. Such knowledge gaps present a major impediment to the development of therapies to treat neurodegenerative diseases. To address this challenge, we propose a new paradigm for understanding ubiquilin function. We hypothesize that ubiquilins directly bind to adrd proteins via the STI1 domain and recruit E3 ligases to promote the formation of biomolecular condensates that protect substrates from degradation. Our hypothesis is supported by substantial preliminary data, including: 1) the first crystal structure of the STI1 domain bound to a substrate with mutagenesis showing how ALS causing mutations disrupt phase separation; 2) in vitro assays linking ubiquitination, phase separation, and protection from degradation; and 3) cellular data showing that UBQLN2 protects substrates from proteasomal degradation in a manner that correlates with E3 ligase recruitment and condensate formation. This proposal will elucidate how STI1 domain binding and E3 ligase recruitment affect cellular fitness and adrd protein stability, phase separation, and function. Our approach utilizes a combination of techniques ranging from structure/function studies to neuronal cell biology, providing a robust combination of mechanistic insights and physiological relevance. Together, these experiments will provide foundational insights into ubiquilin function and fundamentally shift our approach for developing therapeutic intervention in alzheimer's disease and related dementias.