2017 Fiscal Year Final Research Report
Identification of ALS linked FUS mutant induced pathological mechanism by genome-wide gene expression analyses
| Project/Area Number |
15K07918
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | FUS / R495X / ALS / RNA-seq / CLIP-seq / Ribo-seq |
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| Outline of Final Research Achievements |
FUS has been identified as one of causative factors of Amyotrophic lateral sclerosis, however, its pathogenic mechanism is still unclear. To uncover it, I focused on R495X, a familial mutant of FUS, and tried to identify its targets using CLIP-seq and its effects on transcriptome and translatome by RNA-seq and Ribo-seq in genome-wide. I identified that R495X preferentially bound to mRNA in the cytoplasm by CLIP-seq. RNA-seq revealed that R495X had a moderate effect on RNA expression. By Ribo-seq, I found that R495X significantly altered the translation of genes related to mitochondria functions resulted in shortening of mitochondria and neurotoxicity. Importantly, a mutant of R495X, R495X4FL, which reduced an RNA binding ability, partially abrogated the phenotypes of R495X. These results indicate that R495X primarily impairs mitochondria by binding to mRNAs related to its functions. Moreover, my results highlight the importance of its RNA binding property of FUS on neurotoxicity.
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| Free Research Field |
神経科学
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