A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model

Naomi Tsuburaya,Shigeto Ikeda ,Nobuki Kato,Masabumi Shibuya ,Norio Shibata,Takao Fujisawa,Seiichi Nakamura,Tsunehiko Higuchi,Takayoshi Okabe,Tetsuo Nagano,Isao Naguro,Andrii Balia,Naoki Umezawa,Hiroyuki Yamakoshi,Hirotatsu Kojima,Manabu Shimonishi,Hidehiko Nakagawa,Keiko Imamura,Satoshi Yokoshima,Haruhisa Inoue,Kengo Homma,Hidenori Ichijo

doi:10.1038/s41467-018-05127-2

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1mut) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death. However, the importance of SOD1-Derlin-1 interaction in in vitro human model and in vivo mouse model remains to be elucidated. Here, we identify small-molecular-weight compounds that inhibit the SOD1-Derlin-1 interaction by screening approximately 160,000 compounds. The inhibitor prevents 122 types of SOD1mut from interacting with Derlin-1, and significantly ameliorates the ALS pathology both in motoneurons derived from patient induced pluripotent stem cells and in model mice. Our data suggest that the SOD1-Derlin-1 interaction contributes to the pathogenesis of ALS and is a promising drug target for ALS treatment.

Highlights

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder
These findings suggest that the SOD1 mutants (SOD1mut)-Derlin-1 interaction is a common feature of SOD1mut-caused familial ALS (FALS) pathology and that inhibition of this interaction may be a potential target for ALS treatment
To identify the combinations that efficiently generate FRET signal, lysates from HEK293A cells transfected with various combinations of SOD1 and Derlin-1 constructs including each binding site were mixed with the antibodies labeled with either Eu or d2

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. Our data emphasize the importance of the SOD1-Derlin-1 interaction as a common mechanism of motoneuron toxicity in SOD1mut, and we provided a potential mechanism-based ALS treatment. Using a titration assay as the third screening, 44 compounds that inhibited the SOD1-Derlin-1-derived FRET signal in a concentration-dependent manner were further selected as positive compounds (Supplementary Figure 1b, d).

Results

Conclusion