| Project/Area Number |
25430054
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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 |
Nerve anatomy/Neuropathology
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| Research Institution | Meiji Pharmaceutical University |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
ARIMA Kunimasa 国立病院機構小諸高原病院, 院長 (20250227)
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| Project Period (FY) |
2013-04-01 – 2017-03-31
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| Project Status |
Completed (Fiscal Year 2016)
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| Budget Amount *help |
¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | C9orf72 / ALS / FTD / 結合タンパク質 / 標的遺伝子 / 分子ネットワーク / Smcr8 / NNA1 / バイオインフォマティクス / AGTPBP1 / オミックス |
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| Outline of Final Research Achievements |
Expanded GGGGCC repeats located in the first intron of the C9orf72 (C9) gene represent the most common genetic abnormality of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). To date, the molecular mechanism underlying neurodegeneration in C9ALS remains unknown. We studied molecular network of genes and proteins involved in C9ALS pathology from public datasets. We found that C9 repeat RNA-binding proteins play a key role in posttranscriptional RNA processing. Gene expression of extracellular matrix proteins (ECM) is reduced in C9ALS iPSC-derived motor neurons. Genes involved in the regulation of actin cytoskeletons are aberrantly expressed in C9ALS cervical motor neurons. We also identified NNA1 and Smcr8 as novel interactors of C9, linking C9 to autophagy regulation. These results suggest that C9 repeat expansions, which deregulate posttranscriptional RNA processing, disturb the homeostasis of ECM and cytoskeletal dynamics, leading to neurodegeneration in C9ALS.
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