Research Project
10492816
PROJECT SUMMARY/ABSTRACT Perturbations in protein quality control have been implicated in many age-related neurodegenerative diseases, which are typically characterized by the accumulation of aggregated proteins such as a-synuclein. Recent studies have shown that ubiquilin-2 (UBQLN2), a ubiquitin-dependent protein quality control protein, co-localizes with protein aggregates in major causes of Alzheimer?s disease and related dementias (ADRD), including Lewy body dementia and Parkinson?s disease, among others. The interaction between UBQLN2 and disease aggregates implicates UBQLN2 as a potential factor in these disorders. UBQLN2 contains N-terminal ubiquitin- like (UBL) and C-terminal ubiquitin-associated (UBA) domains that allow UBQLN2 to shuttle ubiquitinated substrates to the proteasome for degradation. UBQLN2 may also target proteins for degradation by autophagy, although this is not as well established in the literature. This proposal will build on recent models and reagents developed in our laboratory to explore the role of UBQLN2 in synucleinopathies. Several studies have shown that UBQLN2 co-localizes with a-synuclein aggregates in disease, but it is unknown whether UBQLN2 normally plays a role in handling a-synuclein or the other prominent proteins underlying ADRD. Preliminary studies have shown that UBQLN2 overexpression markedly reduces a-synuclein levels, while UBQLN2 knockdown increases a-synuclein levels. This proposal will define the role of UBQLN2 in clearing a-synuclein, both normally and in disease states. To accomplish this goal, I will use mouse models to investigate the role of UBQLN2 in clearing a-synuclein in vivo and determine if UBQLN2-mediated clearance ameliorates a-synuclein pathology. I will also use cellular models to investigate the mechanism by which UBQLN2 regulates a-synuclein, making use of domain deletion mutants to investigate the role of ubiquitin, chaperone, and proteasome binding domains on UBQLN2 in mediating the clearance of a-synuclein. The proposed studies will lead to a better understanding of the role of protein quality control pathways in neurodegenerative disease and may reveal novel therapeutic targets for age-related dementias. This work will also be foundational to my continued graduate and postdoctoral training as I prepare for a career as an independent scientist.
