2021 Fiscal Year Final Research Report
DCTN1 binds to TDP-43 and regulates TDP-43 aggregation
Project/Area Number |
20K22663
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund |
Review Section |
0702:Biology at cellular to organismal levels, and related fields
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Research Institution | Fukuoka University |
Principal Investigator |
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Project Period (FY) |
2020-09-11 – 2022-03-31
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Keywords | ダイナクチン / ダイニン / TDP-43 / Perry病 / 細胞内輸送 / タンパク質凝集体 / モデルマウス |
Outline of Final Research Achievements |
A major hallmark of several neurodegenerative diseases, including ALS, is cytoplasmic aggregation of TDP-43. Perry disease is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin binds to cytoplasmic dynein and regulates dynein-mediated retrograde transport. Perry disease-linked missense mutations (e.g. p.G71A) impair microtubule-binding abilities of DCTN1. However, how DCTN1 mutations cause TDP-43 proteinopathy remains unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using DCTN1 mutants revealed that the DCTN1 CAP-Gly-basic domain, dynactin domain, and C-terminal region bound to TDP-43. Remarkably, the p.G71A mutation affected TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A induced cytoplasmic aggregation of TDP-43. We thus identified DCTN1 as a new player in TDP-43 transport, providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.
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Free Research Field |
神経科学
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Academic Significance and Societal Importance of the Research Achievements |
TDP-43は、ALSをはじめとする複数の神経変性疾患で見られる異常凝集体の主成分である。本来は核に存在するべきTDP-43を細胞質内で凝集させる病的仕組みは、未解明のままである。我々は、DCTN1(ダイニンと呼ばれるモータータンパク質の運動性を制御するアダプター分子であり、Perry病の原因遺伝子産物)が、TDP-43に結合することを見出した。更に、DCTN1-TDP-43結合の制御異常により、細胞質内凝集体が形成される仕組みの一端を明らかにした。この仕組みが、ALSなどの発症に広く関与する可能性がある。
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