| Project/Area Number |
16K09683
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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 | Meiji Pharmaceutical University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | ポリグルタミン / ALS / FTD / C9orf72 / 凝集 / MLF2 / リピート伸長 / ポリグルタミン病 / 核内凝集体 / ALS/FTD / リピート伸長疾患 / RNA結合タンパク質 / ＡＬＳ / タンパク質凝集 / 神経変性疾患 / ＦＴＤ |
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| Outline of Final Research Achievements |
GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat expansion of C9orf72 leads to the production of dipeptide repeats from the expanded RNA. Here, we searched for proteins that co-aggregate with Gly-Ala (GA) dipeptide repeat as well as polyglutamine (polyQ) in order to identify common interactors of different types of protein aggregates. We screened proteins that colocalized with aggregates of GA repeat and polyQ in Neuro2a cells and found Mlf2 as a common interactor. We found the binding proteins of Mlf2, including some cytoskeletal or nuclear proteins. In the brain, endogenous Mlf2 was localized in the nucleus and the neurites in wild-type mice. However, in a polyQ disease model mice, Mlf2 was observed in the aggregates and its distribution in the neurites was weakened. Thus, it is likely that the function of Mlf2 may be compromised by the pathogenic repeat proteins.
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| Academic Significance and Societal Importance of the Research Achievements |
神経難病と呼ばれる疾患は数多く存在し、治療法が確立されていないものも多い。そのような疾患の一つ、筋萎縮性側索硬化症（ALS）は発症後わずか数年で寝たきりになり、治療薬も限られている。C9orf72遺伝子に存在するGGGGCCリピート配列の異常伸長はALSで最も頻度の高い変異であり、そこから異常なリピートタンパク質が発現する。同様の疾患として、CAGリピート配列の伸長によるポリグルタミン病が以前から知られている。本課題では両疾患群に共通して関わるタンパク質を探索し、複数の神経疾患に関わる重要因子の特定を目指した。そのような因子の候補としてMLF2を見出し、その性状について明らかにした。
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