Therapeutic Targets in the Ubiquitin-proteasome System for Alzheimer's Disease

The appearance of protein aggregates is a common pathological hallmark that is associated with Alzheimer's disease and other major neurodegenerative disorders. Misfolded and damaged proteins that accumulate in neurodegenerative disease can be cleared through the ubiquitin proteasome system (UPS), a highly regulated pathway whose proper function is of paramount importance in the selective degradation of protein. Studies of the UPS have shown that alterations in the activity of this complex system may be contributors in the etiology of specific neurodegenerative disorders. Studies of familial genetic mutations and through experimental manipulation have suggested that a failure to clear toxic proteins through the UPS may exert important effect on the progression of these disorders; in addition, the accumulation of hallmark proteins themselves may in turn impair clearance by this pathway. This review will discuss recent observations indicating that alterations in the function and efficiency of the UPS are contributors in pathogenesis of Alzheimer's disease, and discuss whether modulation of the UPS may be an appropriate therapeutic target in Alzheimer's disease and similar neurological disorders.