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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model
Naomi Tsuburaya1, Kengo Homma1, Tsunehiko Higuchi2
1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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.
Insights
Researchers identified compounds inhibiting the SOD1-Derlin-1 interaction, a key factor in Amyotrophic Lateral Sclerosis (ALS). This discovery offers a promising new drug target for treating ALS.
Area of Science:
- Neuroscience
- Genetics
- Drug Discovery
Background:
- Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease with no effective treatments.
- Mutations in the Cu, Zn superoxide dismutase (SOD1) gene are a known cause of ALS.
- SOD1 mutants (SOD1mut) interact with Derlin-1, leading to motoneuron death.
Purpose of the Study:
- To investigate the role of the SOD1-Derlin-1 interaction in ALS pathogenesis.
- To identify small-molecule inhibitors of the SOD1-Derlin-1 interaction.
- To evaluate the therapeutic potential of these inhibitors in ALS models.
Main Methods:
- Screening of approximately 160,000 small-molecule compounds.
- Assessing the inhibition of SOD1mut-Derlin-1 interaction.
- Evaluating therapeutic efficacy in patient-derived motoneurons and a mouse model of ALS.
Main Results:
- Identification of compounds that effectively inhibit the SOD1-Derlin-1 interaction.
- The inhibitor demonstrated efficacy against 122 types of SOD1mut.
- Significant amelioration of ALS pathology in both in vitro and in vivo models.
Conclusions:
- The SOD1-Derlin-1 interaction is a significant contributor to ALS pathogenesis.
- Targeting this interaction represents a promising therapeutic strategy for ALS.
- Developed inhibitors show potential for future ALS drug development.
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