Wild-Type Human TDP-43 Expression Causes TDP-43 Phosphorylation, Mitochondrial Aggregation, Motor Deficits, and Early Mortality in Transgenic Mice
Ya Fei Xu,Tania F. Gendron,Yong Jie Zhang,Wen Lang Lin,Simon D'Alton,Hong Sheng,Monica Castanedes Casey,Jimei Tong,Joshua Knight,Xin Yu,Rosa Rademakers,Kevin B. Boylan,Mike Hutton,Eileen McGowan,Dennis W. Dickson,Jada Lewis,Leonard Petrucelli +16 more
TLDR
Transgenic mice expressing full-length human TDP-43 (hTDP- 43) driven by the mouse prion promoter are generated to provide a tool to analyze the role of wild-type hT DP-43 in the brain and spinal cord and for studying TDP -43-associated neurotoxicity.Abstract:
Transactivation response DNA-binding protein 43 (TDP-43) is a principal component of ubiquitinated inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions and in amyotrophic lateral sclerosis (ALS). Mutations in TARDBP, the gene encoding TDP-43, are associated with sporadic and familial ALS, yet multiple neurodegenerative diseases exhibit TDP-43 pathology without known TARDBP mutations. While TDP-43 has been ascribed a number of roles in normal biology, including mRNA splicing and transcription regulation, elucidating disease mechanisms associated with this protein is hindered by the lack of models to dissect such functions. We have generated transgenic (TDP-43PrP) mice expressing full-length human TDP-43 (hTDP-43) driven by the mouse prion promoter to provide a tool to analyze the role of wild-type hTDP-43 in the brain and spinal cord. Expression of hTDP-43 caused a dose-dependent downregulation of mouse TDP-43 RNA and protein. Moderate overexpression of hTDP-43 resulted in TDP-43 truncation, increased cytoplasmic and nuclear ubiquitin levels, and intranuclear and cytoplasmic aggregates that were immunopositive for phosphorylated TDP-43. Of note, abnormal juxtanuclear aggregates of mitochondria were observed, accompanied by enhanced levels of Fis1 and phosphorylated DLP1, key components of the mitochondrial fission machinery. Conversely, a marked reduction in mitofusin 1 expression, which plays an essential role in mitochondrial fusion, was observed in TDP-43PrP mice. Finally, TDP-43PrP mice showed reactive gliosis, axonal and myelin degeneration, gait abnormalities, and early lethality. This TDP-43 transgenic line provides a valuable tool for identifying potential roles of wild-type TDP-43 within the CNS and for studying TDP-43-associated neurotoxicity.read more
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Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43
Magdalini Polymenidou,Clotilde Lagier-Tourenne,Kasey R. Hutt,Stephanie C. Huelga,Jacqueline T. Moran,Tiffany Y. Liang,Shuo-Chien Ling,Eveline Sun,Edward Wancewicz,Curt Mazur,Holly B. Kordasiewicz,Yalda Sedaghat,John Paul Donohue,Lily Shiue,C. Frank Bennett,Gene W. Yeo,Don W. Cleveland +16 more
TL;DR: It is found that TDP-43 autoregulates its synthesis, in part by directly binding and enhancing splicing of an intron in the 3′ untranslated region of its own transcript, thereby triggering nonsense-mediated RNA degradation.
Journal ArticleDOI
Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration
TL;DR: Experimental studies are attempting to determine whether TDP43-mediated neurodegeneration results from a gain or a loss of function of the protein, and the distinct possibility of pleotropic or combined effects.
Journal ArticleDOI
TDP-43 regulates its mRNA levels through a negative feedback loop
Youhna M. Ayala,Laura De Conti,S. Eréndira Avendaño-Vázquez,Ashish Dhir,Maurizio Romano,Maurizio Romano,Andrea D’Ambrogio,James R. Tollervey,Jernej Ule,Marco Baralle,Emanuele Buratti,Francisco E. Baralle +11 more
TL;DR: The findings demonstrate that cellular TDP‐43 levels are under tight control and it is likely that disease‐associated T DP‐43 aggregates disrupt TDP43 self‐regulation, thus contributing to pathogenesis.
Journal ArticleDOI
Protein aggregation in amyotrophic lateral sclerosis
TL;DR: Recent advances in the understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS are discussed.
Journal ArticleDOI
ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
Radu Stoica,Kurt J. De Vos,Kurt J. De Vos,Sebastien Paillusson,Sarah M. Mueller,Rosa M. Sancho,Kwok-Fai Lau,Kwok-Fai Lau,Gema Vizcay-Barrena,Wen Lang Lin,Ya Fei Xu,Jada Lewis,Dennis W. Dickson,Leonard Petrucelli,Jacqueline C. Mitchell,Christopher Shaw,Christopher C.J. Miller +16 more
TL;DR: It is demonstrated that the ER-resident protein VAPB interacts with the mitochondrial protein tyrosine phosphatase-interacting protein-51 (PTPIP51) to regulate ER–mitochondria associations and that TDP-43, a protein pathologically linked to amyotrophic lateral sclerosis and fronto-temporal dementia perturbs ER–Mitochondria interactions.
References
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Journal ArticleDOI
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Manuela Neumann,Deepak M. Sampathu,Linda K. Kwong,Adam C. Truax,Matthew Micsenyi,Thomas T. Chou,Jennifer Bruce,Theresa Schuck,Murray Grossman,Christopher M. Clark,Leo McCluskey,Bruce L. Miller,Eliezer Masliah,Ian R. A. Mackenzie,Howard Feldman,Wolfgang Feiden,Hans A. Kretzschmar,John Q. Trojanowski,Virginia M.-Y. Lee +18 more
TL;DR: It is shown that TDP-43 is the major disease protein in both frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis.
Journal ArticleDOI
TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis
Jemeen Sreedharan,Ian P. Blair,Vineeta B. Tripathi,Xun Hu,Caroline Vance,Boris Rogelj,Steven Ackerley,Steven Ackerley,Jennifer C Durnall,Kelly L. Williams,Emanuele Buratti,Francisco E. Baralle,Jacqueline de Belleroche,J. Douglas Mitchell,P. Nigel Leigh,Ammar Al-Chalabi,Christopher C.J. Miller,Christopher C.J. Miller,Garth A. Nicholson,Garth A. Nicholson,Christopher Shaw +20 more
TL;DR: The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.
Journal ArticleDOI
TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Tetsuaki Arai,Masato Hasegawa,Haruhiko Akiyama,Kenji Ikeda,Takashi Nonaka,Hiroshi Mori,David M. A. Mann,Kuniaki Tsuchiya,Mari Yoshida,Yoshio Hashizume,Tatsuro Oda +10 more
TL;DR: The common occurrence of intracellular accumulations of TDP-43 supports the hypothesis that these disorders represent a clinicopathological entity of a single disease, and suggests that they can be newly classified as a proteinopathy of T DP-43.
Journal ArticleDOI
TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis
Edor Kabashi,Paul N. Valdmanis,Patrick A. Dion,Dan Spiegelman,Brendan J. McConkey,Christine Vande Velde,Jean-Pierre Bouchard,Lucette Lacomblez,Ksenia Pochigaeva,François Salachas,Pierre-François Pradat,William Camu,Vincent Meininger,Nicolas Dupré,Nicolas Dupré,Guy A. Rouleau +15 more
TL;DR: Findings further corroborate that TDP-43 is involved in ALS pathogenesis and reports eight missense mutations in nine individuals—six from individuals with sporadic ALS and three from those with familial ALS (FALS)—and a concurring increase of a smaller T DP-43 product.
Journal ArticleDOI
PINK1-dependent recruitment of Parkin to mitochondria in mitophagy
Cristofol Vives-Bauza,Chun Zhou,Yong Huang,Mei Cui,Rosa L.A. de Vries,Jiho Kim,Jessica May,Maja Aleksandra Tocilescu,Wencheng Liu,Han Seok Ko,Jordi Magrané,Darren J. Moore,Darren J. Moore,Valina L. Dawson,Regis Grailhe,Ted M. Dawson,Chenjian Li,Kim Tieu,Serge Przedborski +18 more
TL;DR: It is suggested that Parkin, together with PINK1, modulates mitochondrial trafficking, especially to the perinuclear region, a subcellular area associated with autophagy, which may alter mitochondrial turnover which, in turn, may cause the accumulation of defective mitochondria and, ultimately, neurodegeneration in Parkinson's disease.
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