TY - JOUR
T1 - A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
AU - Tsuburaya, Naomi
AU - Homma, Kengo
AU - Higuchi, Tsunehiko
AU - Balia, Andrii
AU - Yamakoshi, Hiroyuki
AU - Shibata, Norio
AU - Nakamura, Seiichi
AU - Nakagawa, Hidehiko
AU - Ikeda, Shin Ichi
AU - Umezawa, Naoki
AU - Kato, Nobuki
AU - Yokoshima, Satoshi
AU - Shibuya, Masatoshi
AU - Shimonishi, Manabu
AU - Kojima, Hirotatsu
AU - Okabe, Takayoshi
AU - Nagano, Tetsuo
AU - Naguro, Isao
AU - Imamura, Keiko
AU - Inoue, Haruhisa
AU - Fujisawa, Takao
AU - Ichijo, Hidenori
N1 - Funding Information:
We thank H. Nishitoh, H. Kadowaki, and N. Yamaguchi (at The University of Tokyo) for discussion and assistance; Y. Ikegaya (at The University of Tokyo) for the instruction of the intracerebroventricular cannulation; One-stop Sharing Facility Center For Future Drug Discoveries (at The University of Tokyo) for sharing the instrument; and H. Nishina (at Tokyo Medical and Dental University) for the support. We are grateful to K. Matsuzaki (at Nagoya Institute of Technology), N. Ieda, M. Kawaguchi (at Nagoya City University), T. Fukuyama and Y. Beniyama (at Nagoya University) for the support of chemical synthesis. A portion of this study resulted from “Understanding of molecular and environmental bases for brain health” performed under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) (to H.I.). This study was also supported by Grants-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science and MEXT (20229004 and 25221302 to H.I., 26650028 and 16K18513 to K.H.), the Advanced research for medical products Mining Program of the National Institute of Biomedical Innovation (to H.I.), Project for Elucidating and Controlling Mechanisms of Aging and Longevity from Japan Agency for Medical Research and Development (AMED) (JP17gm5010001 to H.I.), as well as the Platform for Drug Discovery, Informatics, and Structural Life Science from AMED (JP17am0101086 to H.K.). This research is partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) (JP17am0101087).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049835014&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049835014&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05127-2
DO - 10.1038/s41467-018-05127-2
M3 - Article
C2 - 29991716
AN - SCOPUS:85049835014
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2668
ER -