Investigation of the Hsp90 co-chaperone, STI1, in cellular resilience and neurodegenerative diseases

Abstract

In neurodegenerative diseases, certain proteins misfold and form toxic aggregates that cause brain matter atrophy, leading to decline in motor and/or cognitive functions. To maintain cellular proteostasis and survival, molecular chaperones regulate protein maturation and help to prevent aberrant protein aggregation. The molecular chaperone Hsp90 regulates hundreds of proteins and interestingly, several of those are misfolded in neurodegenerative diseases. Stress inducible-phosphoprotein-1 (STI1, STIP1), an Hsp90 co-chaperone, orchestrates client protein transfer between chaperones Hsp70 and Hsp90 through physical interactions with both chaperones. Notably, previous work in yeast, worms, and mouse neurons all showed that STI1 protects organisms against stressors and amyloid-like proteotoxicity in vitro. However, the physiological roles of STI1 during aging, and whether STI1 can modulate proteotoxicity and aggregation in mammals is unknown. In this dissertation, we explore whether decreased or increased STI1 levels in mice, can modulate aging and proteostasis responses to misfolded protein stress. Our hypothesis is that modifying intracellular and extracellular levels of STI1, in vivo, affects neuronal resilience during aging, disturbs Hsp90 chaperone machinery function, and modulates levels of protein misfolding and aggregation. We reveal that STI1 knockdown in mice reduces Hsp90 machinery function, and that mice present with age-dependent decline in neuronal resilience in the hippocampus, resulting in memory impairments. Unexpectedly, we find that overexpressing STI1 in an AD mouse model accelerates insoluble Aβ aggregation, resulting in greater levels of neurodegeneration and cognitive impairments. Likewise, STI1 overexpression augments α-synuclein accumulation in a mouse model of synucleinopathy, however, knocking down STI1 attenuated α-synuclein aggregation, improving motor performance. Notably, in both models of proteinopathies, STI1 colocalized with protein aggregates, likely modulating STI1 functions. Since our results suggest that reducing STI1 would be favourable for decreasing protein aggregation, we generated STI1 conditional knockdown mice, to establish whether reducing STI1 after development is tolerable, and indeed, we found that to be the case. Overall, in this thesis we provide a greater understanding of mammalian STI1 in neuronal resilience and protein misfolding in vivo and discover STI1 as a potential therapeutic target for treating protein misfolding diseases in the brain