Heat shock proteins in neurodegenerative disorders and aging

Abstract

Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stress-induced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

Fig. 1

Schematic of Hsp70 (red) and a few of its cofactors. Under physiological conditions, misfolded proteins can induce Hsp70 gene expression and they may be degraded by the ubiquitin proteasome system (UPS) if they are irreparably damaged. During substrate degradation, CHIP binds the C-terminal of Hsp70 and acts as an E3 ubiquitin ligase to mark the protein for removal. During this process, Bag1 binds the ATPase domain at the N-terminal and serves to link the Hsp70/cofactor complex with the UPS. On the other hand, when proteins can be refolded to their native structure and salvaged, Bag-1 binding is blocked by the cochaperone Hip and CHIP binding is blocked by Hop. Hsp40 and Hsp90 may also bind the protein refolding complex and promote ATP-dependent folding activity. Not shown in this figure is the dimerization of some of these proteins. Under conditions of severe proteotoxic stress or loss of homeostasis, proteins may not undergo degradation or refolding and are sequestered in fibrillar deposits, such as Lewy bodies in Parkinson’s disease