title: Differences in protein quality control correlate with phenotype variability in 2 mouse models of familial amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a disease of variable severity in terms of speed of progression of the disease course. We found a similar variability in disease onset and progression of 2 familial ALS mouse strains, despite the fact that they carry the same transgene copy number and express the same amount of mutant SOD1G93A messenger RNA and protein in the central nervous system. Comparative analysis of 2 SOD1G93A mouse strains highlights differences associated with the disease severity that are unrelated to the degree of motor neuron loss but that appear to promote early dysfunction of these cells linked to protein aggregation. Features of fast progressing phenotype are (1) abundant protein aggregates containing mutant SOD1 and multiple chaperones; (2) low basal expression of the chaperone alpha-B-crystallin (CRYAB) and β5 subunits of proteasome; and (3) downregulation of proteasome subunit expression at disease onset. In contrast, high levels of functional chaperones such as cyclophillin-A and CRYAB, combined with delayed alteration of expression of proteasome subunits and the sequestration of TDP43 into aggregates, are features associated with a more slowly progressing pathology. These data support the hypothesis that impairment of protein homeostasis caused by low-soluble chaperone levels, together with malfunction of the proteasome degradation machinery, contributes to accelerate motor neuron dysfunction and progression of disease symptoms. Therefore, modulating the activity of these systems could represent a rational therapeutic strategy for slowing down disease progression in SOD1-related ALS.
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Marino
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Papa
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), "Centro di Eccellenza per lo studio delle Malattie Neurodegenerative" (CEND), Universita' degli Studi di Milano, Milano, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Crippa
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Nardo
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cheroni
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Maria Chiara
authors.initials: MC
authors.lastname: Trolese
authors.affiliation: Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Lauranzano
authors.affiliation: Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Bonetto
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), "Centro di Eccellenza per lo studio delle Malattie Neurodegenerative" (CEND), Universita' degli Studi di Milano, Milano, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Poletti
authors.affiliation: Dipartimento di BioScienze, Universita' degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: DeBiasi
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferraiuolo
authors.affiliation: Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Department of Neuroscience, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy. Electronic address: caterina.bendotti@marionegri.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism; D021984:Cyclophilin A / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D058990:Molecular Targeted Therapy; D009046:Motor Neurons / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D021984:Cyclophilin A; D004268:DNA-Binding Proteins; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D013482:Superoxide Dismutase; C578077:Tardbp protein, mouse; C109415:SOD1 G93A protein
keywords: ALS; Alpha-B-crystallin; Autophagy; Chaperone; Cyclophillin-A; Proteasome; Protein quality control; SOD1G93A transgenic mouse