Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice
| العنوان: | Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice |
|---|---|
| المؤلفون: | Lei Pan, Koichiro Abe, Masayuki Yamamoto, Huifang Shang, Asako Otomo, Masashi Aoki, Mizuki Kubo, Kai Sato, Tetsuro Ishii, Xue Ping Chen, Suzuka Ono, Wakana Onodera, Eiji Warabi, Fumihito Yoshii, Yasuo Uchiyama, Toru Yanagawa, Shun Mitsui, Masato Koike, Shinji Hadano |
| المصدر: | Human Molecular Genetics. 25:3321-3340 |
| بيانات النشر: | Oxford University Press (OUP), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, NF-E2-Related Factor 2, Transgene, SOD1, Mutation, Missense, Mice, Transgenic, Endosomes, Biology, medicine.disease_cause, Pathogenesis, Mice, 03 medical and health sciences, Superoxide Dismutase-1, 0302 clinical medicine, Sequestosome-1 Protein, Autophagy, Genetics, medicine, Animals, Guanine Nucleotide Exchange Factors, Humans, Amyotrophic lateral sclerosis, Molecular Biology, Genetics (clinical), Motor Neurons, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Brain, General Medicine, medicine.disease, NFE2L2, Cell biology, 030104 developmental biology, Proteostasis, Immunology, Lysosomes, 030217 neurology & neurosurgery, Oxidative stress |
| الوصف: | 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. |
| تدمد: | 1460-2083 0964-6906 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c643aef21ae4d6a7db6860d48c2e404aTest https://doi.org/10.1093/hmg/ddw180Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c643aef21ae4d6a7db6860d48c2e404a |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14602083 09646906 |
|---|