Identification of chemical compounds inhibiting SOD1-Derlin-1 interaction for ALS treatment

2015 Fiscal Year Final Research Report

• Project/Area Number: 26650028
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: The University of Tokyo
• Principal Investigator: Homma Kengo 東京大学, 薬学研究科(研究院), 助教 (60708171)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Keywords: ALS / SOD1 / 低分子化合物 / PPI阻害

Outline of Final Research Achievements

ALS is a devastating neurodegenerative disease characterized by the selective motoneuron death. We have previously reported that more than 100 different SOD1 mutants specifically interact with Derlin-1, a component of ERAD machinery. This interaction cause ER stress, leading to the motoneuron death. Motoneuron death induced by SOD1 mutants was significantly attenuated by coexpression of a SOD1-Derlin-1 interaction inhibitory peptide, suggesting that this interaction plays an important role in the pathogenesis of ALS. Therefore, the low molecular weight compounds inhibiting SOD1-Derlin-1 interaction can be used as the novel therapeutic approach for ALS.
Here we screened about 160,000 chemical compounds. Continuous intraventricular administration of one prominent inhibitor has ameliorated disease in a mouse model of ALS, delayed onset significantly and prolonged survival. Our results show the possibilities to establish ALS treatment based on the molecular mechanism.

Free Research Field

生化学