title: ALS mouse model SOD1G93A displays early pathology of sensory small fibers associated to accumulation of a neurotoxic splice variant of peripherin.
abstract: Growing evidence suggests that amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease that primarily affects motor neurons and, though less evidently, other neuronal systems. About 75% of sporadic and familial ALS patients show a subclinical degeneration of small-diameter fibers, as measured by loss of intraepidermal nerve fibers (IENFs), but the underlying biological causes are unknown. Small-diameter fibers are derived from small-diameter sensory neurons, located in dorsal root ganglia (DRG), whose biochemical hallmark is the expression of type III intermediate filament peripherin. We tested here the hypothesis that small-diameter DRG neurons of ALS mouse model SOD1(G93A)suffer from axonal stress and investigated the underlying molecular mechanism. We found that SOD1(G93A)mice display small fiber pathology, as measured by IENF loss, which precedes the onset of the disease. In vitro small-diameter DRG neurons of SOD1(G93A)mice show axonal stress features and accumulation of a peripherin splice variant, named peripherin56, which causes axonal stress through disassembling light and medium neurofilament subunits (NFL and NFM, respectively). Our findings first demonstrate that small-diameter DRG neurons of the ALS mouse model SOD1(G93A)display axonal stress in vitro and in vivo, thus sustaining the hypothesis that the effects of ALS disease spread beyond motor neurons. These results suggest a molecular mechanism for the small fiber pathology found in ALS patients. Finally, our data agree with previous findings, suggesting a key role of peripherin in the ALS pathogenesis, thus highlighting that DRG neurons mirror some dysfunctions found in motor neurons.
authors.affiliation: 3rd Neurology Unit and jenny.sassone@istituto-besta.it glauria@istituto-besta.it.
authors.forename: Jenny
authors.initials: J
authors.lastname: Sassone
authors.affiliation: 3rd Neurology Unit and.
authors.forename: Michela
authors.initials: M
authors.lastname: Taiana
authors.affiliation: 3rd Neurology Unit and.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.affiliation: 3rd Neurology Unit and.
authors.forename: Carla
authors.initials: C
authors.lastname: Porretta-Serapiglia
authors.affiliation: Neuroscience Department, Laboratory of Molecular Neurobiology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri', Animal Facility Fondazione italiana per la ricerca sulla SLA (AriSLA), Milan, Italy and.
authors.forename: Mattia
authors.initials: M
authors.lastname: Freschi
authors.affiliation: 4th Neurology Unit, IRCCS Foundation 'Carlo Besta' Neurological Institute, via Celoria 11, 20133 Milan, Italy, PhD Program in Neuroscience, University of Milan, Bicocca, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bonanno
authors.affiliation: 4th Neurology Unit, IRCCS Foundation 'Carlo Besta' Neurological Institute, via Celoria 11, 20133 Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcuzzo
authors.affiliation: 3rd Neurology Unit and.
authors.forename: Francesca
authors.initials: F
authors.lastname: Caravello
authors.affiliation: Neuroscience Department, Laboratory of Molecular Neurobiology, IRCCS Istituto di Ricerche Farmacologiche 'Mario Negri'.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.affiliation: 3rd Neurology Unit and jenny.sassone@istituto-besta.it glauria@istituto-besta.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
mesh_terms: D000409:Alanine / Q000378:metabolism; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology*; D005786:Gene Expression Regulation; D005998:Glycine / Q000378:metabolism; D006801:Humans; D051379:Mice; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D064531:Peripherins / Q000235:genetics* / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics*
chemical_list: D064531:Peripherins; C579005:Prph protein, mouse; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1; D000409:Alanine; D005998:Glycine