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Review
. 2021 Jan;41(1):202-222.
doi: 10.1002/med.21729. Epub 2020 Aug 25.

The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies

Subhabrata Chaudhury  1 , Bradley M Keegan  1 , Brian S J Blagg  1
Affiliations
Review

The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies

Subhabrata Chaudhury et al. Med Res Rev. 2021 Jan.

Abstract

Heat shock proteins (Hsps) are molecular chaperones that also play important roles in the activation of the heat shock response (HSR). The HSR is an evolutionary conserved and protective mechanism that is used to counter abnormal physiological conditions, stressors, and disease states, such as those exemplified in cancer and/or neurodegeneration. In normal cells, heat shock factor-1 (HSF-1), the transcription factor that regulates the HSR, remains in a dormant multiprotein complex that is formed upon association with chaperones (Hsp90, Hsp70, etc.), co-chaperones, and client proteins. However, under cellular stress, HSF-1 dissociates from Hsp90 and induces the transcriptional upregulation of Hsp70 to afford protection against the encountered cellular stress. As a consequence of both peripheral and central neuropathies, cellular stress occurs and results in the accumulation of unfolded and/or misfolded proteins, which can be counterbalanced by activation of the HSR. Since Hsp90 is the primary regulator of the HSR, modulation of Hsp90 by small molecules represents an attractive therapeutic approach against both peripheral and central neuropathies.

Keywords: HSF-1; Hsp90; chaperones; diabetic peripheral neuropathy; heat shock response; neurodegeneration; neuropathy.

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Figures

Figure 1.
Figure 1.
Mechanism of HSF-1-mediated transcriptional activation
Figure 2.
Figure 2.
Structure of the Hsp90 homodimer
Figure 3.
Figure 3.
The Hsp90 ATPase/protein folding cycle
Figure 4.
Figure 4.
Structures of select N-terminal Hsp90 inhibitors
Figure 5.
Figure 5.
Structures of select C-terminal Hsp90 inhibitors
Figure 6.
Figure 6.
Mechanism of cytoprotection afforded by KU-596 elicitation of the HSR
Figure 7.
Figure 7.
Hsp90-mediated tau oligomerization
Figure 8.
Figure 8.
Chaperone-mediated autophagy versus the ubiquitin-proteasome system for degradation of protein substrates
Figure 9.
Figure 9.
Structures of select Aha1/Hsp90 disruptors
See this image and copyright information in PMC

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