2022/12/21
Niigata University
Keio University
As part of the Takeda Pharmaceutical Company Limited Shonan Incubation Lab project, an industry-academia collaborative research initiative, a joint research group—comprising Associate Professor Mahito Yano of the Department of Brain Functional Morphology, Graduate School of Medical and Dental Sciences, Niigata University; principal investigator Masahiro Nogami of Takeda Pharmaceutical Company Limited; and Professor Hideyuki Okano of the Department of Physiology, Keio University School of Medicine—has successfully demonstrated that the translocation of mutant FUS protein, the product of a causative gene for familial amyotrophic lateral sclerosis (ALS), to cytoplasmic stress granules is dependent on DNA-PK. The group also succeeded in identifying 23 small-molecule compounds that inhibit the translocation of FUS protein to stress granules.
ALS is a progressive neurodegenerative disease characterized by muscle atrophy and weakness, where motor neurons are selectively affected. It is designated as an intractable disease in Japan, for which no effective treatment is currently available. In cell experiments using cells stably expressing wild-type and mutant FUS (with mutations found in familial ALS) tagged with fluorescent proteins, the research group discovered the synergistic, DNA-PK-dependent translocation of FUS protein to the nucleolus and cytoplasmic granules upon DNA damage. Furthermore, using a glioma cell line stably expressing the stress granule marker G3BP1 as a control, the group conducted a screening for small-molecule compounds that selectively inhibit the translocation of mutant FUS to stress granules without inhibiting stress granule formation itself. This screening enables the identification of compounds that can suppress FUS pathology while maintaining cellular defense mechanisms. It was confirmed that some of the compounds obtained from this screening produced similar results for endogenous FUS protein. These findings are expected to contribute to the elucidation of a wide range of molecular pathologies in neurodegenerative diseases, including ALS and intracellular aggregate formation by FUS, as well as to the provision of tools for pathological analysis and the development of new therapeutic methods, including drug discovery. The results of this research were published in the online edition of "Frontiers in Molecular Neuroscience" on December 20, 2022, at 8:00 a.m. (Central European Time).
[Key Findings of This Research]
・Discovered the mechanism by which FUS protein translocates to stress granules in a DNA-PK-dependent manner
・Identified small-molecule compounds that selectively inhibit the translocation of mutant FUS protein to stress granules
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