Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1

Abstract

Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion‐like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome‐maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild‐type protein in a stable dimer and resulting in a loss of chaperone‐like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.

Small heat shock proteins in neurodegenerative diseases

“…Molecularly, overexpression of HSPB1, HSPB5, and HSPB8 has been shown to reduce aggregation of SOD1 in vitro (Patel et al 2005;An et al 2009;Crippa et al 2010;Yerbury et al 2013;Capponi et al 2016). Interestingly, CMT2/dHMN-associated mutants K141N/E were found to have decreased chaperone activity towards SOD1(G93A).…”

“…Intriguingly, genetic overlap is observed between CMT and dHMN as both diseases can be caused by mutations in the same gene and even by the same mutation. Moreover, it was recently demonstrated that some patients with HSPB1 and HSPB8 mutations may have rare forms of ALS or distal myopathy, respectively, further supporting the genetic and clinical heterogeneity (Dierick et al 2007;Capponi et al 2016;Ghaoui et al 2016;Echaniz-Laguna et al 2017b). To date, no effective treatment is available to delay or cure patients with sHSP mutations.…”

Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations

“…Age of onset is usually around 30 years, upper limbs are involved with time, and the rate of progression is slow with a minority of patients requiring a wheelchair in their seventies. So far, 25 HSPB1 mutations have been reported in more than 42 families, and five HSPB8 mutations in approximately nine families [Benndorf et al, 2014;DiVincenzo et al, 2014;Maeda et al, 2014;Ylikallio et al, 2014;Ghaoui et al, 2015;Stancanelli et al, 2015;Ylikallio et al, 2015;Capponi et al, 2016]. When considering HSPB3 (HSPL27) mutations, a unique missense mutation was reported in two dHMN siblings [Kolb et al, 2010].…”

Mutant HSPB1 causes loss of translational repression by binding to PCBP1, an RNA binding protein with a possible role in neurodegenerative disease

“…So far, 26 mutations (including 22 missense mutations) have been found in HSPB1 that are responsible for axonal Charcot-Marie-Tooth neuropathy (CMT2F), distal hereditary motor neuropathy (dHMN) and amyothropic lateral sclerosis (ALS) [7, 11, 14, 27, 49]. Depending on where the mutations are located in the HSPB1 gene, they can have different consequences on the protein function and patient’s clinical outcome.…”