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Review
. 2020 Jul;25(4):655-665.
doi: 10.1007/s12192-020-01099-9. Epub 2020 Apr 16.

Mutations in HspB1 and hereditary neuropathies

Lydia K Muranova  1 , Maria V Sudnitsyna  1 , Sergei V Strelkov  2 , Nikolai B Gusev  3
Affiliations
Review

Mutations in HspB1 and hereditary neuropathies

Lydia K Muranova et al. Cell Stress Chaperones. 2020 Jul.

Abstract

Charcot-Marie-Tooth (CMT) disease is major hereditary neuropathy. CMT has been linked to mutations in a range of proteins, including the small heat shock protein HspB1. Here we review the properties of several HspB1 mutants associated with CMT. In vitro, mutations in the N-terminal domain lead to a formation of larger HspB1 oligomers when compared with the wild-type (WT) protein. These mutants are resistant to phosphorylation-induced dissociation and reveal lower chaperone-like activity than the WT on a range of model substrates. Mutations in the α-crystallin domain lead to the formation of yet larger HspB1 oligomers tending to dissociate at low protein concentration and having variable chaperone-like activity. Mutations in the conservative IPV motif within the C-terminal domain induce the formation of very large oligomers with low chaperone-like activity. Most mutants interact with a partner small heat shock protein, HspB6, in a manner different from that of the WT protein. The link between the altered physico-chemical properties and the pathological CMT phenotype is a subject of discussion. Certain HspB1 mutations appear to have an effect on cytoskeletal elements such as intermediate filaments and/or microtubules, and by this means damage the axonal transport. In addition, mutations of HspB1 can affect the metabolism in astroglia and indirectly modulate the viability of motor neurons. While the mechanisms of pathological mutations in HspB1 are likely to vary greatly across different mutations, further in vitro and in vivo studies are required for a better understanding of the CMT disease at molecular level.

Keywords: Chaperone-like activity; Congenital diseases; Mutations; Oligomeric structure; Protein phosphorylation; Protein-protein interactions; Small heat shock proteins.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
a Schematic drawing of HspB1. NTD is marked gray, ACD including seven β-strands is marked orange, and CTD is marked green. Location of phosphorylation sites, conservative octapeptide in the NTD, and conservative tripeptide IPV in the CTD are marked red. b Three-dimensional structure of HspB1 ACD dimer with indication of β7 strands which form an antiparallel interface (PDB entry 4mjh). Locations of certain point mutations associated with the Charcot-Marie-Tooth disease are marked
Fig. 2
Fig. 2
a Proposed mechanisms of CMT pathogenesis induced by HspB1 mutations. HspB1 mutations affect the cytoskeleton of neurons. Specifically, such mutations can induce overstabilization of microtubules. These changes are followed by tubulin deacetylation and microtubule depolymerization during later stages of disease. In addition mutations of HspB1 can induce the disruption of neurofilament network and/or affect neurofilament phosphorylation and anterograde transportation of neurofilaments. b Mutations of HspB1 can affect astroglia metabolism and induce the production of reactive oxygen substances leading to axon degeneration. See text for details
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