Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential

The maintenance of protein homeostasis is essential for neuronal survival and function; however, it progressively declines with age, predisposing the brain to neurodegenerative diseases. Molecular chaperones Hsp70 and Hsp90 are key guardians of proteostasis, pivotally regulating protein folding, refolding, and degradation under both physiological and stress conditions. This review integrates an overview of the structural features, isoforms, and mechanistic interactions of Hsp70 and Hsp90. It highlights how their dysfunction contributes to the pathogenesis of major neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. We first examine the architecture and ATP-driven chaperone cycles of Hsp70 and Hsp90, their co-chaperone networks, and the feedback regulation by the Heat Shock Factor-1 pathway. We then discuss evidence linking age-related declines in chaperone expression and HSF-1 activity to proteostasis collapse and neuronal vulnerability. The review particularly examines how Hsp70 and Hsp90 differentially influence pathogenic protein aggregation (e.g., tau, α-synuclein, TDP-43, and mutant huntingtin) and how this balance is altered in the aging brain. Regarding therapeutic approaches, we summarize current strategies targeting these chaperones, including small-molecule modulators of Hsp70 and Hsp90, co-chaperone inhibitors, and recombinant chaperone therapy, which has shown to restore proteostasis and cognitive function in experimental models. These emerging interventions underscore the dual nature of Hsp70/Hsp90 systems, acting as both protectors and potential contributors to neurodegeneration, depending on their regulation and interaction context. By linking molecular chaperone biology to aging and translational therapeutics, this review establishes a framework for developing precision approaches that enhance proteostasis capacity, delay age-associated neurodegeneration, and promote healthy brain aging.