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.
TL;DR: In this paper, the authors proposed targeting neurotoxic synergies between tau and TDP-43 as a new therapeutic strategy for Alzheimer's disease with comorbid TDP43 pathology.
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TL;DR: The structure of TDP-43, its main physiological functions, the possible pathogenesis and how TDP -43 provides a new pathway to treat neurodegenerative diseases are described.
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Paola Saveri,Stefania Magri,Emanuela Maderna,Francesca Balistreri,Raffaella Lombardi,Claudia Ciano,Fabio Moda,Barbara Garavaglia,Chiara Reale,Giuseppe Lauria Pinter,Franco Taroni,Davide Pareyson,Chiara Pisciotta +12 more
TL;DR: In this article , the authors describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms of the disease.
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Molecular Dissection of TDP-43 as a Leading Cause of ALS/FTLD
TL;DR: The cellular processes involved in the pathogeneses of ALS and FTLD, such as post-translational modifications, RNA metabolism, liquid–liquid phase separation, proteolysis, and the potential prion-like propagation propensity of the TDP-43 inclusions are described.
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Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons
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References
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Journal ArticleDOI
Cytoplasmic aggregates of dynactin in iPSC-derived tyrosine hydroxylase-positive neurons from a patient with Perry syndrome
Takayasu Mishima,Takayasu Mishima,Taizo Ishikawa,Keiko Imamura,Takayuki Kondo,Yasushi Koshiba,Ryosuke Takahashi,Jun Takahashi,Akihiro Watanabe,Naoki Fujii,Yoshio Tsuboi,Haruhisa Inoue +11 more
TL;DR: Th-positive neurons from Perry syndrome iPSCs recapitulated an aspect of the disease phenotype of Perry syndrome, and metaiodobenzylguanidine cardiac scintigraphy also showed decreased uptake.
Journal ArticleDOI
P150glued-associated disorders are caused by activation of intrinsic apoptotic pathway.
Kei-Ichi Ishikawa,Shinji Saiki,Norihiko Furuya,Daisuke Yamada,Yoko Imamichi,Yuanzhe Li,Sumihiro Kawajiri,Hironori Sasaki,Masato Koike,Yoshio Tsuboi,Nobutaka Hattori +10 more
TL;DR: It is suggested that both p150glued gain-of-toxic-function and loss- of-physiological-function can cause apoptosis and may underlie the pathogenesis of p 150glued-associated disorders.
Journal ArticleDOI
Genetic analysis of ALS cases in the isolated island population of Malta.
Rebecca M. Borg,Maia Farrugia Wismayer,Karl Bonavia,Andrew Farrugia Wismayer,Malcolm Vella,Joke J.F.A. van Vugt,Brendan J. Kenna,Kevin P. Kenna,Neville Vassallo,Jan H. Veldink,Ruben J. Cauchi +10 more
TL;DR: In this article, the authors investigated the epidemiology and genetic profile of Maltese patients with ALS, identified throughout a 2-year window, finding that 40% of patients with sporadic ALS had a rare and deleterious variant or repeat expansion in an ALS-associated gene, whilst the genetic cause of two thirds of fALS cases could not be pinpointed to known ALS genes or risk loci.
Journal ArticleDOI
Reduced TDP-43 Expression Improves Neuronal Activities in a Drosophila Model of Perry Syndrome
Yuka Hosaka,Tsuyoshi Inoshita,Kahori Shiba-Fukushima,Changxu Cui,Taku Arano,Yuzuru Imai,Nobutaka Hattori +6 more
TL;DR: It is reported that a reduction in TDP-43 protein levels alleviates the synaptic defects of neurons expressing the Perry mutant p150G50R in Drosophila, suggesting that the stagnation of axonal transport by dynactin mutations promotes T DP-43 aggregation and interferes with the dynamics of DCVs and synaptic activities.
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Modeling Parkinson's Disease and Atypical Parkinsonian Syndromes Using Induced Pluripotent Stem Cells.
TL;DR: Recent findings from iPSC-based modeling of PD and several atypical parkinsonian syndromes including multiple system atrophy, frontotemporal dementia and parkinsonism linked to chromosome 17 and Perry syndrome are summarized.
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