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The Role of Heat Shock Proteins in Neuroprotection

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Heat shock proteins (or stress proteins) are evolutionary conserved proteins found in all living organism and cell types. Heat shock proteins (Hsps) belong to five families: Hsp100, Hsp90, Hsp70, Hsp60, and the so-called small heat shock proteins. Their primary function is the maintenance of proteome ...

Heat shock proteins (or stress proteins) are evolutionary conserved proteins found in all living organism and cell types. Heat shock proteins (Hsps) belong to five families: Hsp100, Hsp90, Hsp70, Hsp60, and the so-called small heat shock proteins. Their primary function is the maintenance of proteome integrity and protein homeostasis (proteostasis) of the cells. Most Hsps act as molecular chaperones and regulate the biosynthesis, folding/unfolding, transport and assembly of cellular proteins. Following cellular stress, they protect misfolded proteins against aggregation and facilitate protein refolding. When protein folding fails, they assist in the proteasomal degradation of polypeptides. On the other hand, Hsps exert their protective role at several levels not linked exclusively to their chaperone function. They regulate membrane quality control, as amphitropic heat shock proteins can bind to membrane lipids directly and stabilize the lipid phase of the membranes. The membrane association of Hsps can antagonize the membrane perturbing effects of stress conditions, underlying their pivotal role in cellular stress management. Hsps regulate cellular redox homeostasis and decrease the damaging effect of oxidative stress. They can inhibit certain steps of the apoptotic pathway and they also regulate inflammatory responses.

Heat shock proteins are elevated following various forms of stress, such as heat, heavy metals, ethanol, hypoxia, ischemia, and they are also deregulated in several diseases and infections, indicating their primary role in cell protection. The level and chaperone activity of heat shock proteins decline with age, correlating with a loss in the capacity of cells to maintain protein homeostasis. It is, therefore, foreseeable that the prevalence of diseases with enhanced protein aggregation, such as Alzheimer’s disease (AD), Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease and other amyloidopathies, increases with age. However, several studies have demonstrated the neuroprotective effect of elevating Hsp levels in models of neurodegenerative disease. For example certain symptoms in a transgenic mouse model of Alzheimer’s disease can be ameliorated by overexpressing HSPB1 in brain or administering small molecules that induce Hsp expression). Thus, Hsps are pharmacologically relevant and could have therapeutic potential in several human diseases. Although logical in principle, clinical application has been limited by the high threshold for stress-induced upregulation of Hsps in neurons, suppression by the disease process itself and toxicity of certain classes of inducers. Further work is needed to exploit Hsps as a therapeutic target, including identifying pharmaceuticals with favourable CNS bioavailability and safety profile and understanding the mechanisms underlying neuroprotection.

This Research Topic aims to provide an overview of our current knowledge on the protective role of Hsps in the nervous system and particular neural cell types. In doing so, the pathway to pharmacological intervention will be further developed in a variety of neurological disorders upstream and downstream in signalling networks involving Hsps. We welcome Original Research papers, Review articles and brief communications addressing the molecular mechanisms and therapeutic potential of Hsps in neurological disorders


Keywords: Heat shock proteins, chaperons, Hsp-mediated neuroprotection, molecular mechanism of Hsps action, Hsps and neurological diseases


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