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ポリグルタミン病、ALS、脊髄小脳変性症、その他の神経変性疾患 1
Polyglutamine Diseases, ALS, SCD, Other Neurodegenerative Disorder 1

開催日 2014/9/11
時間 9:00 - 10:00
会場 Room I(311+312)
Chairperson(s) 秦野 伸二 / Shinji Hadano (東海大学医学部基礎医学系分子生命科学 / Department of Molecular Life Sciences, Tokai University School of Medicine, Japan)
小野寺 理 / Osamu Onodera (新潟大学脳研究所 / Brain Research Institute, Niigata University, Japan)

Loss of p62/SQSTM1, an autophagy substrate, aggravates motor dysfunction in a SOD1H46R-expressing mouse ALS model

  • O1-I-1-1
  • 秦野 伸二 / Shinji Hadano:1 潘 雷 / Lei Pan:1 大友 麻子 / Asako Otomo:1 阿部 幸一郎 / Koichiro Abe:1 小池 正人 / Masato Koike:2 内山 安男 / Yasuo Uchiyama:2 青木 正志 / Masashi Aoki:3 石井 哲郎 / Tetsuro Ishii:4 柳川 徹 / Toru Yanagawa:4 Shang Hui-Fang / Hui-Fang Shang:5 吉井 文均 / Fumihito Yoshii:6 
  • 1:東海大・医・分子生命 / Dept Mol Life Sci, Tokai Univ Sch of Med, Kanagawa, Japan 2:順大院・細胞神経 / Juntendo Univ Grad Sch of Med, Tokyo, Japan 3:東北大院・神内 / Tohoku Univ Grade Sch of Med, Miyagi, Japan 4:筑波大・医 / Univ of Tsukuba, Ibaraki, Japan 5:四川大華西医院、成都、中国 / Sichuan Univ, Chengdu, China 6:東海大・医・神内 / Tokai Univ Sch of Med, Kanagawa, Japan 

Recent studies have revealed missense variants and/or mutations in SQSTM1 in familial as well as sporadic amyotrophic lateral sclerosis (ALS). SQSTM1 encodes p62/SQSTM1 that regulates the selective-autophagy via association with ubiquitinated proteins. Notably, abundant p62-positive inclusions in the spinal cord are a typical pathological feature of ALS. Thus, p62 might play a crucial role in maintenance and/or survival of motor neurons. However, the mechanism by which mutations in SQSTM1 cause ALS is still unclear. In this study, we investigate a role of p62 in the onset and/or progression of ALS using ALS mouse models. We generated SOD1H46R transgenic mice on a Sqstm1-null background by crossing Sqstm1-KO mice with the SOD1H46R mouse line expressing familial ALS-linked SOD1H46R under the control of inherent human SOD1 promoter. Body weight and survival of each animal were monitored. Motor coordination and balance were also measured by a balance-beam test to evaluate the motor dysfunction in the mice. Sqstm1-/- mice did not show any gross abnormal phenotypes during the experimental period (~30 weeks). By contrast, SOD1H46R and Sqstm1+/-;SOD1H46R mice both exhibited progressive motor dysfunction and paralysis with average life spans of 174 and 175 days, respectively. Remarkably, Sqstm1-/-;SOD1H46R mice showed a significantly-shorter life span of 154 days. Furthermore, a balance-beam test revealed that motor dysfunction in Sqstm1-/-;SOD1H46R mice occurs at an approximately 3 weeks earlier than that in SOD1H46R mice. These results indicate that lack of p62/SQSTM1 exacerbates motor dysfunction in SOD1H46R mice. Thus, loss of function of p62/SQSTM1 is, at least in part, associated with motor neuron diseases.

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