Effects of lysosomal instability on the non-apoptotic Purkinje cell death

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08522
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Juntendo University
• Principal Investigator: Koike Masato 順天堂大学, 医学(系)研究科(研究院), 教授 (80347210)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: オートファジー / リソソーム / カテプシン / ゴルジ体 / 小脳 / プルキンエ細胞 / 細胞死 / 軸索変性

Outline of Final Research Achievements

We generated mice with a cathepsin D (CTSD) deficiency specifically in the Purkinje (PCs) and basket cells (BCs) and compared their phenotypes with those of PC and BC-selective Atg7-deficient mice. In both strains of mice, PCs underwent degeneration, but the CTSD-deficient PCs disappeared more rapidly than their Atg7-deficient counterparts. The neuronal cell death of CTSD- and Atg7-deficient PCs was distinct from apoptosis. Axonal spheroids and the swelling of presynaptic terminals of PCs were more pronounced in Atg7-deficient PCs than in CTSD-deficient PCs.These results suggested that PCs were more vulnerable to CTSD deficiency in lysosomes than to autophagy impairment, and this vulnerability does not depend on the severity of axonal swelling.
We also generated mice with a Golgi pH regulator (GPHR) deficiency specifically in the PCs and BCs and found that PCs from the mutant mice exhibited axonal degeneration and progressive cell loss.

Free Research Field

神経細胞生物学

Academic Significance and Societal Importance of the Research Achievements

ヒトではカテプシンDの遺伝子変異は最も重篤なタイプの神経性セロイドリポフスチン蓄積症発症に関与する。同患者では、カテプシンDの活性が低いほど症状が重篤であるが、全ての症例において小脳失調が認められる。本研究成果は、神経性セロイドリポフスチン蓄積症における神経変性のメカニズムの一端を明らかにするもので、同疾患の理解につながる社会的意義を有する。
ゴルジ体の機能不全については、これまでゴルジ体を特異的に制御する薬剤が存在せず、神経変性疾患におけるゴルジ体の構造異常がその原因なのかを知る術がなかった。今回のGPHR欠損マウスの解析で、ゴルジ体の異常と神経変性との直接的な因果関係を明らかにした。