Multidimensional Analyses of the Central Nervous System Pathophysiology of Repeat Expansion Disease: Focusing on Myotonic Dystrophy
| Project/Area Number |
19K07992
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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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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 筋強直性ジストロフィ / RNA / スプライシング / 中枢神経 / 認知機能 / 筋強直性ジストロフィー / 大脳 / 小脳 / 神経変性疾患 / 神経ネットワーク / リピート病 / 脳 / 網羅的解析 |
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| Outline of Research at the Start |
神経変性疾患の細胞内分子レベルの解明は進んだものの、残された重要な課題のひとつは脳領域・細胞選択性障害のメカニズムである。本研究ではRNA病としての病態理解が進んだ筋強直性ジストロフィーを主な対象とし、脳領域ごとに網羅的トランスクリプトームやエピゲノム解析などを行い、領域選択性の分子機序解明を目指す。さらに脊髄小脳変性症等との比較を通じ、リピート病に共通の新たな病態の解明を目指す。また、自閉症スペクトラム障害などで注目されているネットワークの機能異常が存在するか、実際の患者で、近年解析技術の進歩の著しい脳画像・脳磁図などを用いた神経ネットワーク活動解析を行い、病態との関連を検討する。
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| Outline of Final Research Achievements |
The ultimate goal of this study was to elucidate the mechanisms of region-selectivity, which remain a crucial issue in the study of neurodegenerative diseases. Myotonic dystrophy (DM) was chosen as the primary focus of the study, as the understanding of its pathogenesis as an RNA disease is very advanced. We performed a comprehensive RNAseq analysis of each brain region using autopsied brains. We identified many splice abnormalities, including those previously reported, in the temporal lobe. Cerebellar-specific abnormalities were also identified. Inter-regional similarities were revealed between frontal and temporal lobes. RNAseq analysis was also performed on the liver to compare the differences between organs. We accumulated neuropsychological and MRI data and clarified the clinical characteristics of DM patients.
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| Academic Significance and Societal Importance of the Research Achievements |
リピート病のひとつである筋強直性ジストロフィーを対象として、中枢神経におけるRNA異常の病態を網羅的解析により明らかにした。この成果は、他のリピート病や変性疾患での解析に役立つ基礎的データとなることが期待される。また、明らかにされた画像や神経心理学的特徴は、患者の臨床評価、治験におけるアウトカムメジャーとしても役立つと考えられる。
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Report
(4 results)
Research Products
(28 results)
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[Journal Article] Cardiac conduction disorders as markers of cardiac events in myotonic dystrophy type 1.2020
Author(s)
2.Itoh H, Hisamatsu T, Tamura T, Segawa K, Takahashi T, Takada H, Kuru S, Wada C, Suzuki M, Suwazono S, Sasaki S, Okumura K, Horie M, Takahashi MP, Matumura T.
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Journal Title
J Am Heart Assoc.
Volume: 9
Issue: 17
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Straightjacket/α2δ3 deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1.2019
Author(s)
Plantie E, Nakamori M, Renaud Y, Huguet A, Choquet C, Dondi C, Miquerol L, Takahashi M, Gourdon G, Junion G, Jagla T, Zmojdzian M, Jagla K
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Journal Title
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Cardiac conduction disorders as markers of cardiac events but not sudden death in myotonic dystrophy type 1.2019
Author(s)
Itoh h, Hisamatsu T, Tamura T, Segawa K, Takahash T, Takada H, Kuru S, Wada C, Suzuki M, Suwazono S, Sasaki S, Okumura K, Horie M, Takahashi M, Matumura T.
Organizer
The 12th International Myotonic Dystrophy Consortium Meeting
Related Report
Int'l Joint Research
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