Mechanism of neuronal cell death in GM2 gangliosidosis

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460389
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: The University of Tokushima
• Principal Investigator: TSUJI Daisuke 徳島大学, 大学院医歯薬学研究部, 助教 (00423400)
• Co-Investigator(Kenkyū-buntansha): ITOH Kohji 徳島大学, 大学院医歯薬学研究部, 教授 (00184656)
• Co-Investigator(Renkei-kenkyūsha): URANO Yasuteru 東京大学, 大学院医学系研究科, 教授 (20292956)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: リソソーム / オートファジー / 糖脂質 / リソソーム病 / iPS細胞

Outline of Final Research Achievements

GM2 gangliosidoses are lysosomal β-hexosaminidase (Hex) deficiency involving excessive accumulation of undegraded substrates, including GM2 ganglioside, and progressive neurodegeneration.
In this study, we generated iPS cell from Tay-Sachs disease (TSD) patient fibroblast, and demonstrated the abnormalities of signaling in TSD neurons. We found differences in PI3K and autophagy signaling in GM2 gangliosidosis model when compared to normal control. In addition, we observed activation of TFEB in lysosomal storage disorders model mice with neuronal manifestations. These results suggest that mTORC1 inactivation and the increase of autophagy were dependent on down-regulation of PI3K signaling. Furthermore, replacement of Hex rescued abnormal signaling in GM2 gangliosidosis models. These findings may represent a mechanism in linking cell death observed in GM2 gangliosidosis neurons.

Free Research Field

病態生化学