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Polyglutamin Diseases

開催日 2014/9/12
時間 9:00 - 10:00
会場 Room I(311+312)
Chairperson(s) 内山 安男 / Yasuo Uchiyama (順天堂大学医学研究科 神経疾患病態構造学講座 / Department of Cellular and Molecular Neuropathology Juntendo University Graduate School of Medicine, Japan)
永井 義隆 / Yoshitaka Nagai (独立行政法人国立精神・神経医療研究センター 神経研究所 疾病研究第四部 / Department of Degenerative Neurological Diseases, National Center of Neurology and Psychiatry, Japan)

p62/SQSTM1 plays a protective role in the autophagic clearance of polyglutamine aggregates in polyglutamine disease model flies

  • O2-I-1-2
  • 齊藤 勇二 / Yuji Saitoh:1 藤掛 伸宏 / Nobuhiro Fujikake:1 岡本 佑馬 / Yuma Okamoto:1 和田 圭司 / Keiji Wada:1 永井 義隆Yoshitaka Nagai 
  • 1:国立精神・神経医療研究センター / National Center of Neurology and Psychiatry, Japan 

The formation of aggregates and the accumulation of ubiquitinated proteins are key events in the pathogenic cascades of many neurodegenerative diseases. Therefore, the clearance of these pathogenic proteins could be a potential treatment for neurodegenerative diseases. The autophagy-lysosome system is an intrinsic non-selective protein degradation system, which can engulf even large aggregates and degrade them. Because p62/SQSTM1 plays a physiological role in selectively degrading ubiquitinated proteins, including large aggregates, by the autophagy-lysosome system, prompt and efficient clearance using p62 could be a therapeutic strategy for neurodegenerative diseases. However, whether this physiological role of p62 is also maintained in pathogenic conditions, such as those in many neurodegenerative diseases, is still unknown. To elucidate the role of p62 in such pathogenic conditions, as well as the interactions of p62 with other molecules in vivo, we used Drosophila models in our study, which have the advantage of the ease of genetic analysis. We found that p62 predominantly colocalizes with cytosolic polyglutamine aggregates in polyglutamine disease model flies, which express a truncated form of the mutant MJD protein (MJDtr-Q78). Loss of p62 function resulted in the exacerbation of eye degeneration in these flies. Immunohistochemical analyses revealed the enhanced accumulation of cytosolic aggregates by p62 knockdown in MJDtr-Q78 flies. On the other hand, knockdown of Autophagy-related genes (Atgs) resulted in similar phenotypic exacerbation to p62 knockdown. Knockdown of both p62 and Atg did not show any additive effects in the MJDtr-Q78 flies, implying that p62 function is mediated by the autophagy-lysosome system. Biochemical analyses showed that loss of p62 function delays the degradation of the MJDtr-Q78 protein, including its aggregates. We therefore conclude that p62 plays a protective role against polyglutamine induced neurodegeneration, by the autophagic clearance of polyglutamine aggregates in vivo. Moreover, our study demonstrates the potential of p62 as a therapeutic target for the polyglutamine diseases.

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