Action and mutations of molecular chaperones

Molecular chaperones have essential roles in many cellular processes, including protein folding, targeting, transport, degradation, and signal transduction. Conditions of stress are characterized by a robust increase in the synthesis of heat shock proteins (HSPs) that are crucial for recovery from stress-induced protein damage. Almost all HSPs, classified into six main families on the basis of their molecular mass, function as molecular chaperones, and the number of diseases that are known to be caused by their mutations are increasing (21,231). Under certain pathological conditions, the capacity of the protein quality control machinery (activation of molecular chaperones, UPP, and lysosome-mediated autophagy) is exceeded and misfolded proteins accumulate to dangerous levels. Accumulation of the aggregation prone proteins activates signal transduction pathways that control cell death, including JNK pathway that controls viability of a cell in various models of PD and HD.

The role of molecular chaperones in specific neurodegenerative diseases has been recently reviewed (21).

In AD, several in vitro studies and animal models suggest direct interaction between chaperones (HSP 28, 70, 72, etc.) with Ap, which might regulate the formation of toxic Ap assemblies. Cross-talk between chaperones and the UPS might be pivotal in regulating the deposition and toxicity of tau. HSP 70 and others interact with hyperphosphorylated tau in human brain, facilitate tau ubiquitination, enhance the levels of insoluble tau (232), and in vitro suppresses tau-induced cell death (233).

In PD, HSP 70 in a cell model decreased the number of cells containing inclusion bodies, although with no effect on cell viability (234). It decreased insoluble high-molecular synuclein and suppressed its toxicity (235), suggesting that HSP 70 and others may have protective roles in PD (236).

In familial ALS, HSP 70 and other chaperones reduce the toxicity of mutant SOD-1, decrease its aggregation, and enhance survival. Overexpression of both HSP 70 and 40 in the presence of mutant SOS-1 in a cell model results in synergistic reduction of aggregate formation (192).

In polyglutamine diseases, the effect of chaperones on the aggregates of expanded proteins has shown inhibition or delay of Huntingtin aggregates, thus modulating neurodegeneration in various animal models (237-239).

It is likely that molecular chaperones facilitate neuroprotection by functioning at various levels that might not be linked exclusively to their direct effects on protein aggregation, but their ability to interfere with OS and block apoptotic signaling pathways should not be overlooked. The major chaperone HSP 72 can interfere with these signaling pathways, thus promoting survival. It might be possible that several chaper-one actions might be required to impede tissue pathogenesis in vivo, and molecular chaperones may increasingly become new targets for the therapy of neurodegenerative diseases (231).

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