Mutations in HspB1 and hereditary neuropathies

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.

A weakened interface in the P182L variant of HSP27 associated with severe Charcot‐Marie‐Tooth neuropathy causes aberrant binding to interacting proteins

“…Dysregulation of the activity or expression of HSP27 can result in debilitating diseases, including cancers (Ciocca & Calderwood, 2005; Straume et al, 2012), neurodegenerative diseases (Outeiro et al, 2006), and neuropathies (Evgrafov et al, 2004). More than 30 heritable HSP27 mutations are implicated in Charcot‐Marie‐Tooth (CMT) disease (Nefedova et al, 2015; Adriaenssens et al, 2017; Echaniz‐Laguna et al, 2017; Muranova et al, 2020; Vendredy et al, 2020), a group of neuropathies that affects ca . 1 in 2,500 individuals and is the most common inherited disorder involving the peripheral nervous system (Barisic et al, 2008; Timmerman et al, 2014).…”

A novel HSPB1 mutation associated with a late onset CMT2 phenotype: Case presentation and systematic review of the literature

“…4 Heat shock proteins (HSPs) are a group of ubiquitously expressed molecular chaperons with crucial roles in the response to cellular stress, proteostasis, and apoptosis. 7,9 The relative specificity of HSP27 mutations for peripheral nerves, and, potentially, for muscle, 10,11 has not yet been explained, but it may implicate HSPs involvement in cell-specific functions, such as cytoskeletal integrity. 12 HSPs structure 13 is highly conserved through evolution and is characterized by the presence of a hydrophobic N-terminal region with a phosphorylation domain (WDFP) which is critical for protein oligomerization, an α-crystallin domain containing β-sheets and mediating dimer formation, and a flexible C-terminal region ( Figure 1C).…”

“…4,5 Following the original description by Evgrafov et al, 4 more than 18 pathogenic mutations spanning across the whole HSPB1 gene have been reported. 6,7 As a result, the ability to diagnose CMT2F/dHMN2 and understand the genotypephenotype correlations that could inform about the natural history of the disease are rapidly expanding.…”

Small Hsps as Therapeutic Targets of Cystic Fibrosis Transmembrane Conductance Regulator Protein

“…In cases of irreversibly impaired polypeptides, HspB1, together with the other chaperones, can promote their ubiquitination and proteasomal degradation machinery [ 60 , 61 ]. In unstressed cells, different oligomeric and phosphorylated forms of HspB1 [ 62 , 63 ] interact with numerous different client proteins in order to modulate their maturation, activity or half-life [ 31 , 64 , 65 ]. In humans, HspB1 mutants can cause neuronal pathologies, such as distal hereditary motor neuropathy and hereditary peripheral neuropathy, also known as Charcot–Marie–Tooth disease type 2F [ 66 , 67 ].…”