Dctn1 binds to tdp-43 and regulates tdp-43 aggregation
Manami Deshimaru,Mariko Kinoshita-Kawada,Kaori Kubota,Takuya Watanabe,Yasuyoshi Tanaka,Saito Hirano,Fumiyoshi Ishidate,Masaki Hiramoto,Mitsuru Ishikawa,Yoshinari Uehara,Hideyuki Okano,Shinichi Hirose,Shinsuke Fujioka,Katsunori Iwasaki,Junichi Yuasa-Kawada,Takayasu Mishima,Yoshio Tsuboi +16 more
TLDR
In this paper, the authors used a panel of truncated mutants to identify a new player in TDP-43 cytoplasmic-nuclear transport, and showed that dysregulation of DCTN1-TDP43 interactions triggers mislocalization and aggregation of TDP43, thus providing insights into the pathological mechanisms of Perry disease.Abstract:
A common pathological hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis, is cytoplasmic mislocalization and aggregation of nuclear RNA-binding protein TDP-43. Perry disease, which displays inherited atypical parkinsonism, is a type of TDP-43 proteinopathy. The causative gene DCTN1 encodes the largest subunit of the dynactin complex. Dynactin associates with the microtubule-based motor cytoplasmic dynein and is required for dynein-mediated long-distance retrograde transport. Perry disease-linked missense mutations (e.g., p.G71A) reside within the CAP-Gly domain and impair the microtubule-binding abilities of DCTN1. However, molecular mechanisms by which such DCTN1 mutations cause TDP-43 proteinopathy remain unclear. We found that DCTN1 bound to TDP-43. Biochemical analysis using a panel of truncated mutants revealed that the DCTN1 CAP-Gly-basic supradomain, dynactin domain, and C-terminal region interacted with TDP-43, preferentially through its C-terminal region. Remarkably, the p.G71A mutation affected the TDP-43-interacting ability of DCTN1. Overexpression of DCTN1G71A, the dynactin-domain fragment, or C-terminal fragment, but not the CAP-Gly-basic fragment, induced cytoplasmic mislocalization and aggregation of TDP-43, suggesting functional modularity among TDP-43-interacting domains of DCTN1. We thus identified 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, thus providing insights into the pathological mechanisms of Perry disease and other TDP-43 proteinopathies.read more
Citations
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DCTN1 mutation associated parkinsonism: case series of three new families with perry syndrome
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TL;DR: Three unrelated individuals with genetically confirmed Perry syndrome associated with autosomal dominant family histories of parkinsonism are discussed, one of which is currently receiving genetic counselling with a view to arranging predictive testing.
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