title: Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transgenic ALS models. We generated SOD1H46Rmice either on a Nfe2l2-null, Sqstm1-null, or Sqstm1/Als2-double null background. Loss of SQSTM1 but not NFE2L2 exacerbated disease symptoms. A simultaneous inactivation of SQSTM1 and ALS2 further accelerated the onset of disease. Biochemical analyses revealed that loss of SQSTM1 increased the level of insoluble SOD1 at the intermediate stage of the disease, whereas no further elevation occurred at the end-stage. Notably, absence of SQSTM1 rather suppressed the mutant SOD1-dependent accumulation of insoluble polyubiquitinated proteins, while ALS2 loss enhanced it. Histopathological examinations demonstrated that loss of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons. Since SQSTM1 loss is more detrimental to SOD1H46Rmice than lack of ALS2, the selective accumulation of such aggregates in neurons might be more insulting than the biochemically-detectable insoluble proteins. Collectively, two ALS-linked factors, SQSTM1 and ALS2, have distinct but additive protective roles against mutant SOD1-mediated toxicity by modulating neuronal proteostasis possibly through the autophagy-endolysosomal system.
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan shinji@is.icc.u-tokai.ac.jp.|Research Center for Brain and Nervous Diseases, Tokai University Graduate School of Medicine, Isehara, Kanagawa, Japan.|The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hadano
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Mitsui
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Lei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.|The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.|Micro/Nano Technology Center, Tokai University, Hiratsuka, Kanagawa, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Otomo
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Kubo
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Suzuka
authors.initials: S
authors.lastname: Ono
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Wakana
authors.initials: W
authors.lastname: Onodera
authors.affiliation: Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Abe
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: XuePing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Faculty of Medicine, University of Tsukuba, Tennoudai, Tsukuba, Ibaraki, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yanagawa
authors.affiliation: Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Shang
authors.affiliation: The Institute of Medical Sciences, Tokai University, Isehara, Kanagawa, Japan.|Department of Neurology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Fumihito
authors.initials: F
authors.lastname: Yoshii
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001343:Autophagy / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D011992:Endosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D000071456:Sequestosome-1 Protein / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C512358:Als2 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C000606290:SOD1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; C109415:SOD1 G93A protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1