2021 Fiscal Year Final Research Report
Establishment of a Perry syndrome disease model using human induced pluripotent stem cells
| Project/Area Number |
18K15471
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 52020:Neurology-related
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| Research Institution | Fukuoka University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2022-03-31
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| Keywords | Perry症候群 / Perry病 / DCTN1 / TDP-43 / 疾患モデル / iPS細胞 |
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| Outline of Final Research Achievements |
We reported two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. With regard to basic research, our heterozygous Dctn1 G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, by TH immunostaining, thereby exhibiting multiple features of Perry disease (Perry syndrome). Furthermore, we found that dynactin1 bound to TDP-43. Biochemical analysis revealed that the dynactin CAP-Gly-basic supra-domain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. We thus revealed DCTN1 as a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP-43 interactions triggers mislocalization and aggregation of TDP-43.
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| Free Research Field |
脳神経内科
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| Academic Significance and Societal Importance of the Research Achievements |
Perry病（Perry症候群）はパーキンソニズム、うつやアパシー、体重減少、中枢性呼吸障害の4徴候を有する常染色体優性（顕性）遺伝の神経変性疾患で、2009年にDCTN1遺伝子変異が発見された。また、病理学的には、筋萎縮性側索硬化症（ALS）などと同様にTDP-43プロテイノパチーに分類される。我々は、Perry病（Perry症候群）の国際診断基準を作成し、Perry症候群からPerry病への名称変更を提唱した。Perry病（Perry症候群）の研究は、パーキンソン病やALSなどの神経変性疾患の病態解明や治療薬開発だけでなく、うつ病や肥満などのコモンディジーズの研究にも寄与する。
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