title: 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.
authors: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.|VIB Department of Molecular Genetics, Peripheral Neuropathy Group, Born Bunge Foundation, University of Antwerp, Antwerp, Belgium.
authors: Simona
authors: S
authors: Capponi
authors: VIB Department of Molecular Genetics, Peripheral Neuropathy Group, Born Bunge Foundation, University of Antwerp, Antwerp, Belgium.
authors: Thomas
authors: T
authors: Geuens
authors: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.
authors: Alessandro
authors: A
authors: Geroldi
authors: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.|COU Medical Genetics, IRCCS AOU San Martino IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Paola
authors: P
authors: Origone
authors: Department of Health Science, University of Genoa, Genoa, Italy.
authors: Simonetta
authors: S
authors: Verdiani
authors: Section of Medicinal Chemistry, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy.
authors: Elena
authors: E
authors: Cichero
authors: VIB Department of Molecular Genetics, Peripheral Neuropathy Group, Born Bunge Foundation, University of Antwerp, Antwerp, Belgium.
authors: Elias
authors: E
authors: Adriaenssens
authors: VIB Department of Molecular Genetics, Peripheral Neuropathy Group, Born Bunge Foundation, University of Antwerp, Antwerp, Belgium.
authors: Vicky
authors: V
authors: De Winter
authors: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, University of Genova, Genoa, Italy.
authors: Monica
authors: M
authors: Bandettini di Poggio
authors: Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.|Laboratory of Molecular Genetics, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy.
authors: Marco
authors: M
authors: Barberis
authors: Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy.|Azienda Ospedaliero Universitaria Città della Salute e della Scienza, Turin, Italy.
authors: Adriano
authors: A
authors: Chiò
authors: Section of Medicinal Chemistry, Department of Pharmacy, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, Italy.
authors: Paola
authors: P
authors: Fossa
authors: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.|COU Medical Genetics, IRCCS AOU San Martino IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Paola
authors: P
authors: Mandich
authors: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, Section of Medical Genetics, University of Genoa, Genoa, Italy.|COU Medical Genetics, IRCCS AOU San Martino IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors: Emilia
authors: E
authors: Bellone
authors: VIB Department of Molecular Genetics, Peripheral Neuropathy Group, Born Bunge Foundation, University of Antwerp, Antwerp, Belgium. vincent.timmerman@molgen.vib-ua.be.
authors: Vincent
authors: V
authors: Timmerman
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D055551:HSP27 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006801:Humans; D007558:Italy; D008875:Middle Aged; D018832:Molecular Chaperones; D009154:Mutation; D055503:Protein Multimerization
chemical_list: D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones
keywords: HSPB1; chaperone activity; molecular modelling; sALS