Title: Potential roles for ubiquilin 1 in Alzheimer's disease pathogenesis
Description: Genetic and functional studies have indicated potential roles for ubiquilin 1 (UBQLN1) in Alzheimer's disease (AD) pathogenesis. Whether UBQLN1's involvement is due to a direct interaction with known AD-related proteins or to other less obvious pathways requires further investigation and is the primary focus of this dissertation. To determine how UBQLN1 might affect the major biochemical pathways involved in AD pathogenesis, and particularly the pathological accumulation of cerebral Aβ, we focused on the potential effects of UBQLN1 down-regulation and overexpression on APP processing and γ-secretase. UBQLN1 down-regulation resulted in a decrease in APP holoprotein levels, an increase in the secretion of sAPPα, total sAPP, and Aβ40, an increase in the ratio of mature to immature APP, and an increase in APP cell surface levels. UBQLN1 TV1 (full-length) and TV2 (lacking exon 8) overexpression decreased the ratio of mature to immature APP; TV1 overexpression increased cell surface levels of APP; TV2 overexpression significantly decreased levels of extracellular Aβ40 and intracellular Aβ42; and neither TV1 nor TV2 affected γ-secretase activity. Collectively, these results support a model in which UBQLN1 acts as a "gatekeeper" for the maturation and trafficking of APP through the secretory pathway to the cell surface. A potential role for UBQLN1 in AD pathogenesis may be modulating the trafficking of UBQLN1-related proteins to the cell surface.

Previous studies have also suggested that UBQLN has a protective effect during ER stress and the unfolded protein response (UPR) and that an impaired ER stress response can potentially contribute to the death of neuronal populations observed in AD pathogenesis. We down-regulated UBQLN1 or overexpressed UBQLN1 transcript variants during ER stress to assess effects on the UPR and UPR-associated neuronal cell death. Our results suggest that overexpression of TV1, TV2, or TV3 (lacking exons 2-4) exerts a protective effect during the UPR by attenuating CHOP induction and enhancing cell viability. In contrast, down-regulation of UBQLN1 did not affect CHOP mRNA induction, but instead increased PDI mRNA levels. Another potential role for UBQLN1 in AD pathogenesis may be preventing activation of apoptotic pathways that ultimately lead to the neuronal cell death observed in AD pathogenesis.