Journal ArticleDOI
Triad of TDP43 control in neurodegeneration: autoregulation, localization and aggregation.
Paraskevi Tziortzouda,Paraskevi Tziortzouda,Ludo Van Den Bosch,Ludo Van Den Bosch,Frank Hirth +4 more
TLDR
Tziortzouda, Van Den Bosch and Hirth as discussed by the authors described three intrinsic mechanisms that control TARDBP levels and localization and are altered to drive pathology, including autoregulation, nucleocytoplasmic transport and phase transition.Abstract:
Cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP43; also known as TARDBP or TDP-43) is a key pathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP43 typically resides in the nucleus but can shuttle between the nucleus and the cytoplasm to exert its multiple functions, which include regulation of the splicing, trafficking and stabilization of RNA. Cytoplasmic mislocalization and nuclear loss of TDP43 have both been associated with ALS and FTD, suggesting that calibrated levels and correct localization of TDP43 — achieved through an autoregulatory loop and tightly controlled nucleocytoplasmic transport — safeguard its normal function. Furthermore, TDP43 can undergo phase transitions, including its dispersion into liquid droplets and its accumulation into irreversible cytoplasmic aggregates. Thus, autoregulation, nucleocytoplasmic transport and phase transition are all part of an intrinsic control system regulating the physiological levels and localization of TDP43, and together are essential for the cellular homeostasis that is affected in neurodegenerative disease. Accumulation of TAR DNA-binding protein 43 (TDP43) in the neuronal cytoplasm and its loss from the nucleus are characteristic features of several neurodegenerative diseases. Tziortzouda, Van Den Bosch and Hirth describe three intrinsic mechanisms that control TDP43 levels and localization and are altered to drive pathology.read more
Citations
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Journal ArticleDOI
TDP-43 condensation properties specify its RNA-binding and regulatory repertoire
Martina Hallegger,Martina Hallegger,Anob M. Chakrabarti,Flora C.Y. Lee,Flora C.Y. Lee,Bo Lim Lee,Aram G. Amalietti,Aram G. Amalietti,Hana M. Odeh,Katie E. Copley,Jack D. Rubien,Bede Portz,Klara Kuret,Ina Huppertz,Frédérique Rau,Frédérique Rau,Rickie Patani,Rickie Patani,Nicolas L. Fawzi,James Shorter,Nicholas M. Luscombe,Nicholas M. Luscombe,Jernej Ule,Jernej Ule +23 more
TL;DR: In this paper, a series of TDP-43 C-terminal domain (CTD) variants exhibited a gradient of low to high condensation propensity, as observed in vitro and by nuclear mobility and foci formation.
Journal ArticleDOI
Disease‐linked TDP‐43 hyperphosphorylation suppresses TDP‐43 condensation and aggregation
Lara A Gruijs da Silva,Francesca Simonetti,Saskia Hutten,Henrick Riemenschneider,Erin L. Sternburg,Lisa M. Pietrek,Jakob Gebel,Volker Dötsch,Dieter Edbauer,Gerhard Hummer,Lukas S. Stelzl,Dorothee Dormann +11 more
TL;DR: Multi‐scale molecular dynamics simulations reveal reduced homotypic interactions of TDP‐43 low‐complexity domains through enhanced solvation of phosphomimetic residues, and speculate that T DP‐43 hyperphosphorylation may be a protective cellular response to counteract TDP•43 aggregation.
Posted ContentDOI
Disease-linked TDP-43 hyperphosphorylation suppresses TDP-43 condensation and aggregation
da Silva Lg,Simonetti F,Simonetti F,Hutten S,Riemenschneider H,Sternburg El,Lisa M. Pietrek,Jakob Gebel,Dötsch,Dieter Edbauer,Gerhard Hummer,Gerhard Hummer,Lukas S. Stelzl,Dorothee Dormann,Dorothee Dormann +14 more
TL;DR: This article showed that TDP-43 hyperphosphorylation by Casein kinase 1δ or C-terminal phosphomimetic mutations surprisingly reduced phase separation and aggregation, and rendered the protein more liquid-like and dynamic.
Journal ArticleDOI
Regulation of liquid-liquid phase separation with focus on post-translational modifications.
TL;DR: In this paper, a review of the regulatory effects of post-translational modification (PTM) and RNA and molecular chaperones in liquid-liquid phase separation (LLPS) is presented.
Journal ArticleDOI
Post-translational modifications on RNA-binding proteins: accelerators, brakes, or passengers in neurodegeneration?
TL;DR: In this paper , post-translational modifications (PTMs) have been used to regulate RNA-binding proteins (RBPs), which allow the cell to quickly and efficiently respond to cellular and environmental stimuli.
References
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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.
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Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS
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TL;DR: It is found that repeat expansion in C9ORF72 is a major cause of both FTD and ALS, suggesting multiple disease mechanisms.
Journal ArticleDOI
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
Alan E. Renton,Elisa Majounie,Adrian James Waite,Javier Simón-Sánchez,Javier Simón-Sánchez,Sara Rollinson,J. Raphael Gibbs,J. Raphael Gibbs,Jennifer C. Schymick,Hannu Laaksovirta,John C. van Swieten,John C. van Swieten,Liisa Myllykangas,Hannu Kalimo,Anders Paetau,Yevgeniya Abramzon,Anne M. Remes,Alice Kaganovich,Sonja W. Scholz,Sonja W. Scholz,Sonja W. Scholz,Jamie Duckworth,Jinhui Ding,Daniel W. Harmer,Dena G. Hernandez,Dena G. Hernandez,Janel O. Johnson,Janel O. Johnson,Kin Y. Mok,Mina Ryten,Danyah Trabzuni,Rita Guerreiro,Richard W. Orrell,James Neal,Alexandra Murray,J. P. Pearson,Iris E. Jansen,David Sondervan,Harro Seelaar,Derek J. Blake,Kate Young,Nicola Halliwell,Janis Bennion Callister,Greg Toulson,Anna Richardson,Alexander Gerhard,Julie S. Snowden,David M. A. Mann,David Neary,Mike A. Nalls,Terhi Peuralinna,Lilja Jansson,Veli-Matti Isoviita,Anna-Lotta Kaivorinne,Maarit Hölttä-Vuori,Elina Ikonen,Raimo Sulkava,Michael Benatar,Joanne Wuu,Adriano Chiò,Gabriella Restagno,Giuseppe Borghero,Mario Sabatelli,David Heckerman,Ekaterina Rogaeva,Lorne Zinman,Jeffrey D. Rothstein,Michael Sendtner,Carsten Drepper,Evan E. Eichler,Can Alkan,Ziedulla Abdullaev,Svetlana Pack,Amalia Dutra,Evgenia Pak,John Hardy,Andrew B. Singleton,Nigel Williams,Peter Heutink,Stuart Pickering-Brown,Huw R. Morris,Huw R. Morris,Huw R. Morris,Pentti J. Tienari,Bryan J. Traynor,Bryan J. Traynor +85 more
TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Liquid phase condensation in cell physiology and disease.
TL;DR: The findings together suggest that several membrane-less organelles have been shown to exhibit a concentration threshold for assembly, a hallmark of phase separation, and represent liquid-phase condensates, which form via a biologically regulated (liquid-liquid) phase separation process.
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.
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