Simona Capponi , Thomas Geuens, Alessandro Geroldi, Paola Origone, Simonetta Verdiani, Elena Cichero, Elias Adriaenssens, Vicky De Winter, Monica Bandettini di Poggio, Marco Barberis, Adriano Chiò, Paola Fossa, Paola Mandich, Emilia Bellone and Vincent Timmerman.
Genetic discoveries in Amyotrophic Lateral Sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the aetiology of most sporadic cases rem ains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and non-neuronal cells and seeding of misfolded protein with prion-like propagation. In this scenario, the This article is protected by copyright. All rights reserved. 3 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 eq uilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identif ying 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.