Therapeutic strategy for ALS with nucleic acid technology focusing on the vulnerability of TDP-43 autoregulation
| Project/Area Number |
17K09751
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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 |
Neurology
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| Research Institution | Niigata University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
石原 智彦 新潟大学, 医歯学総合病院, 講師 (70612232)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | 筋萎縮性側索硬化症 / TDP-43 / アンチセンスオリゴ / ALS |
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| Outline of Final Research Achievements |
In amyotrophic lateral sclerosis (ALS), the nuclear protein TDP-43 accumulates in the cytoplasm. TDP-43 binds to its pre-mRNA, induces alternative splicing, and autoregulates its expression levels. Here, we first constructed a mathematical model and predicted that transcriptional redundancy that underpins TDP-43 autoregulation could drive TDP-43 pathology. Then, we used an antisense oligo to suppress TDP-43 alternative splicing and manifested transcriptional redundancy. As a result, in the mouse spinal cord, the increase and fragmentation of insoluble TDP-43 and decrease in the number of motor neurons were observed. These results, which recapitulate part of the ALS pathology, suggested that this alternative splicing could be a promising therapeutic target for ALS.
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| Academic Significance and Societal Importance of the Research Achievements |
筋萎縮性側索硬化症（ALS）は、病理学的にTDP-43の凝集と蓄積によって特徴付けられる。しかし、このTDP-43病理がどのように駆動されているのかはほとんど分かっていない。本研究は、TDP-43量調節に潜在する脆弱性に着目し、遺伝子を改変せずに、マウス脊髄において、TDP-43の病態を模倣させた。これにより、TDP-43量調節に潜在する脆弱性が、ALSの治療標的となる可能性を示した。これらの成果は、難病であるALSの治療法の開発に向けた基盤を提供する。
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Report
(4 results)
Research Products
(12 results)
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[Journal Article] Phosphorylated TDP-43 aggregates in skeletal and cardiac muscle are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions.2019
Author(s)
Mori F, Tada M, Kon T, Miki Y, Tanji K, Kurotaki H, Tomiyama M, Ishihara T, Onodera O, Kakita A, Wakabayashi K.
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Journal Title
Acta Neuropatholgica Communications
Volume: 7
Issue: 1
Pages: 165-165
DOI
Related Report
Peer Reviewed / Open Access
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