Journal
HUMAN MUTATION
Volume 37, Issue 11, Pages 1202-1208Publisher
WILEY
DOI: 10.1002/humu.23062
Keywords
sALS; HSPB1; chaperone activity; molecular modelling
Categories
Funding
- Galliera Genetic Bank, member of the Network Telethon of Genetic Biobanks [GTB12001A]
- Telethon Italy
- University of Genoa (Italy)
- ACMT-rete Association
- European Community [259867]
- Joint Programme Neurodegenerative Disease Research (Italian Ministry of Education and University, Strength Project)
- Associazionc Piemontese per l'Assistenza alla SLA (APASLA), Torino, Italy
- Association Beige contre les Maladies Neuromusculaires (ABMM)
- Fund for Scientific Research Flanders (FWO)
- EC [2012-305121]
- EWO
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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.
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