Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: Cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice

Shinji Hadano, Shun Mitsui, Lei Pan, Asako Otomo, Mizuki Kubo, Kai Sato, Suzuka Ono, Wakana Onodera, Koichiro Abe, Xue Ping Chen, Masato Koike, Yasuo Uchiyama, Masashi Aoki, Eiji Warabi, Masayuki Yamamoto, Tetsuro Ishii, Toru Yanagawa, Hui Fang Shang, Fumihito Yoshii

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


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 SOD1H46R mice 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 SOD1H46R mice 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.

Original languageEnglish
Pages (from-to)3321-3340
Number of pages20
JournalHuman molecular genetics
Issue number15
Publication statusPublished - 2016 Aug 1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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