Investigation of the role of autophagy in Neuronal Ceroid Lipofuscinoses

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15198
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: Juntendo University
• Principal Investigator: Junji Yamaguchi 順天堂大学, 大学院医学研究科, 助教 (30875282)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: カテプシンD / オートファジー / p62

Outline of Final Research Achievements

It has been reported that autophagy is closely involved in pathogenesis of neuronal ceroid lipofuscin (NCL), however, its details remain unknown. In this research, using cathepsin D (CTSD)-deficient mice, one type of NCL model mice, we showed that abnormal lysosomes with degenerated membranes were degraded by selective autophagy. Furthermore, to investigate the role of autophagy in CTSD-deficient mice, we generated the central nerve tissue specific CTSD/ Atg7-double deficient mice, NCL model mice impaired autophagy. In these mice, there were few abnormal lysosomes surrounded by autophagic vacuoles. However, we found that some of lysosomes were captured into p62 bodies formed by the impaired autophagic machinery. These results are important for investigating the degeneration and degraded mechanism of lysosomes in vivo, and useful for understanding of detailed NCL pathogenesis.

Free Research Field

神経科学

Academic Significance and Societal Importance of the Research Achievements

リソソームは細胞内の不要物質を分解する重要なオルガネラであり、リソソーム蓄積症をはじめ多くの疾患に関与する。近年、リソソーム自身も損傷を受けた際に選択的オートファジーの標的になることが示されているが、生体内における詳細な機構は未だ多くはわかっていない。CTSD欠損マウス神経細胞内では上記の現象が散見され、生体内におけるリソソームの損傷や修復を理解する上で重要なモデルとなることが分かった。また、NCL病態内で見られる異常リソソームは膜の変性が生じた後にp62やNBR1を介した選択的オートファジーによって処理される可能性を示した。