INVESTIGATING THE ROLE OF UBIQUILIN2 IN AGE-RELATED NEURODEGENERATION

Abstract

Brain accumulation of Ubiquilin2 (UBQLN2) is a shared feature of neurodegenerative diseases including Alzheimer's disease, Lewy Body Dementia, Frontotemporal Dementia (FTD) and polyglutamine expansion disorders such as Huntington disease (HD). UBQLN2's involvement in neurodegeneration reflects the fact that it normally helps maintain protein quality control, principally in protein degradation by the proteasome. Rare mutations in UBQLN2 also directly cause neurodegeneration on the FTD/ALS spectrum. Unfortunately, UBQLN2's normal function in health and its dysfunction in disease remain poorly understood. To explore UBQLN2-mediated disease we employed protein biochemistry, cell-based studies, longitudinal fluorescence microscopy and mouse models of ALS/FTD and HD. Data from in vitro studies of full length UBQLN2, expression studies in cultured neurons, and transgenic mice expressing wildtype (WT) or mutant (MUT) UBQLN2 support the view that the protein is intrinsically prone to form aggregates and that pathogenic mutations can accelerate this process. Studies of UBQLN2 deleted of functional domains implicate a specific domain in driving aggregation of both wild type and mutant UBQLN2. In transgenic mice expressing MUT-UBQLN2, the protein becomes sequestered in large aggregates within neurons throughout the central nervous system including cortex, hippocampus, cerebellum and spinal cord. Mutant mice also exhibit aberrant TDP43 localization, a common pathological hallmark of ALS/FTD generally and of UBQLN2-mediated disease specifically. In contrast, WT-UBQLN2 largely remains diffusely distributed in neurons, though some neurons display spherical puncta enriched for UBQLN2. When overexpressed in a mouse model of HD, WT-UBQLN2 nearly abolishes nuclear aggregates of the HD protein, a characteristic disease feature of HD. In the presence of mutant HD protein, UBQLN2 also moves from its normal cytoplasmic location to the nucleus of affected neurons. Our results support a dominant toxic effect of MUT-UBQLN2 driving disease pathogenesis, associated with aggregation of the protein. Our results further support the view that UBQLN2 normally functions in neurons to help maintain protein homeostasis; whether partial loss of this quality control function contributes to disease pathogenesis remains unknown. Accordingly, ongoing studies are focused in part on evaluating the differences between wild type and mutant forms of UBQLN2 in maintaining neuronal protein homeostasis.