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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Tau and TDP-43 synergy: a novel therapeutic target for sporadic late-onset Alzheimer's disease.
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Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons
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References
More filters
Journal ArticleDOI
Neural differentiation of human embryonic stem cells induced by the transgene-mediated overexpression of single transcription factors.
Misako Matsushita,Yuhki Nakatake,Itaru Arai,Keiji Ibata,Kazuhisa Kohda,Sravan Kumar Goparaju,Miyako Murakami,Miki Sakota,Nana Chikazawa-Nohtomi,Shigeru B. H. Ko,Takanori Kanai,Michisuke Yuzaki,Minoru S.H. Ko +12 more
TL;DR: Results indicate that over-expression of each of these five TFs can override the pluripotency-specific gene network and force hESCs to differentiate into neurons.
Journal ArticleDOI
Japanese family with parkinsonism, depression, weight loss, and central hypoventilation.
TL;DR: The Fukuoka 1 family shares many clinical and pathologic features with five previously reported kindreds from North America and Europe, suggesting that this syndrome has a worldwide distribution and can occur in different ethnic populations.
Journal ArticleDOI
Nuclear pore complex tethers to the cytoskeleton.
TL;DR: The nuclear envelope is tethered to the cytoskeleton, primarily via motor proteins (dynein and kinesins) which are linked, most importantly, to the cytoplasmic filament protein of the nuclear pore complex, Nup358, by the adaptor BicD2.
Journal ArticleDOI
A crucial role for Arf6 in the response of commissural axons to Slit
Mariko Kinoshita-Kawada,Mariko Kinoshita-Kawada,Mariko Kinoshita-Kawada,Hiroshi Hasegawa,Tsunaki Hongu,Shigeru Yanagi,Yasunori Kanaho,Ichiro Masai,Takayasu Mishima,Xiaoping Chen,Yoshio Tsuboi,Yi Rao,Junichi Yuasa-Kawada,Jane Y. Wu +13 more
TL;DR: It is found that a Robo1 endocytosis-triggered and Arf6-mediated positive-feedback strengthens the Slit response in commissural axons upon their midline crossing and provides insights into endocytic trafficking-mediated mechanisms for spatiotemporally controlled axonal responses.
Journal ArticleDOI
Location of disorder in coiled coil proteins is influenced by its biological role and subcellular localization: a GO-based study on human proteome
TL;DR: The study shows that the in silico approach of mapping of disorder in or around coiled coils in other biological systems or organisms can be applied to understand and rationalize the mode of action of these dynamic motifs.
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