Heat shock proteins: Multiple neuroprotective functions and implications for neurologic disease

Heat shock proteins (Hsps) comprise a heterogeneous group of highly conserved molecules that are a critical component of proteostasis. Some Hsps are constitutively expressed in cells to promote proper folding and assembly of polypeptides. However, most Hsps are also rapidly induced in response to cellular stress, including oxidative stress and ischemic injury that results in the accumulation of denatured proteins (figure 1). Hsps provide a first line of defense against accumulation of misfolded, aggregation-prone proteins; their neuroprotective effects also include inhibition of apoptosis, cytoskeletal protection, and immune modulation. Hsps are present in the inclusions that characterize several neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease. Mutations of Hsps have been linked to some forms of distal hereditary motor neuronopathy, axonal Charcot-Marie-Tooth type 2 (CMT2) disease, myofibrillary myopathy, and progressive spastic paraparesis. Hsps are among the most potent suppressors of neurodegeneration in animal models. Thus, Hsps provide a potential target for protective pharmacotherapy in many neurologic disorders. The multiple functions and dynamics of Hsps and their involvement in neurologic diseases have been extensively reviewed.1,–,15 Figure 1 Heat shock response and chaperone functions of heat shock proteins (Hsps) Accumulation of misfolded proteins during cellular stress is the basic trigger for expression of Hsps, via a feedback loop involving heat shock factor (HSF)-1. HSF-1 is kept in an inactive, monomeric state in the cytoplasm by association with Hsp90. In response to accumulation of misfolded proteins, HSF-1 dissociates from Hsps 90, undergoes trimerization and translocation to the nucleus, and binds to heat shock elements (HSE) in Hsp genes, activating the production of Hsp70, Hsp40, and small Hsps such as Hsp27. The chaperone activity of Hsp90 and Hsp70 requires dynamic conformational changes and adenosine triphosphate (ATP) hydrolysis. Hsp40 interacts with Hsp70, coupling substrate binding with ATP hydrolysis. Once transcribed, small Hsps such as Hsp27 form large oligomeric structures; …