Journal ArticleDOI
TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
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TLDR
TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies because of the striking functional and structural similarities of these proteins, which imply that abnormal RNA metabolism is a pivotal event in neurodegeneration.Abstract:
Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.read more
Citations
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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
The amyloid state of proteins in human diseases
TL;DR: This work summarizes studies of structure and nucleation of amyloid and relate these to observations on amyloids polymorphism, prion strains, coaggregation of pathogenic proteins in tissues, and mechanisms of toxicity and transmissibility.
Journal ArticleDOI
Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis.
TL;DR: It is presented the case here that these two processes are intimately linked, with disease-initiated perturbation of either leading to further deviation of both protein and RNA homeostasis through a feedforward loop including cell-to-cell prion-like spread that may represent the mechanism for relentless disease progression.
Journal ArticleDOI
The C9orf72 GGGGCC Repeat Is Translated into Aggregating Dipeptide-Repeat Proteins in FTLD/ALS
Kohji Mori,Shih-Ming Weng,Thomas Arzberger,Stephanie May,Kristin Rentzsch,Elisabeth Kremmer,Bettina Schmid,Bettina Schmid,Hans A. Kretzschmar,Marc Cruts,Christine Van Broeckhoven,Christian Haass,Christian Haass,Dieter Edbauer,Dieter Edbauer +14 more
TL;DR: It is found that characteristic intracellular inclusions of misfolded proteins define C9orf72 pathology, but the core proteins of the majority of inclusions are still unknown, and a new class of proteins links a common genetic mutation to the predominant pathology in certain neurodegenerative diseases.
Journal ArticleDOI
Exome Sequencing Reveals VCP Mutations as a Cause of Familial ALS
Janel O. Johnson,Jessica Mandrioli,Michael Benatar,Yevgeniya Abramzon,Vivianna M. Van Deerlin,John Q. Trojanowski,J. Raphael Gibbs,J. Raphael Gibbs,Maura Brunetti,Susan Gronka,Joanne Wuu,Jinhui Ding,Leo McCluskey,Maria Martinez-Lage,Dana Falcone,Dena G. Hernandez,Dena G. Hernandez,Sampath Arepalli,Sean Chong,Jennifer C. Schymick,Jeffrey D. Rothstein,Francesco Landi,Yong Dong Wang,Andrea Calvo,Gabriele Mora,Mario Sabatelli,Maria Rosaria Monsurrò,Stefania Battistini,Fabrizio Salvi,Rossella Spataro,Patrizia Sola,Giuseppe Borghero,Giuliana Galassi,Sonja W. Scholz,Sonja W. Scholz,J. Paul Taylor,Gabriella Restagno,Adriano Chiò,Bryan J. Traynor,Bryan J. Traynor +39 more
TL;DR: Exome sequencing data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neurons degeneration.
References
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Journal ArticleDOI
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis
TL;DR: Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.
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
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Thomas J. Kwiatkowski,D. A. Bosco,D. A. Bosco,A. L. LeClerc,A. L. LeClerc,Eric Tamrazian,Charles R. Vanderburg,Carsten Russ,Carsten Russ,A. Davis,James M. Gilchrist,E. J. Kasarskis,Theodore L. Munsat,Paul N. Valdmanis,Guy A. Rouleau,Betsy A. Hosler,Pietro Cortelli,P. J. De Jong,Yuko Yoshinaga,Jonathan L. Haines,Margaret A. Pericak-Vance,Jianhua Yan,Nicola Ticozzi,Nicola Ticozzi,Nicola Ticozzi,Teepu Siddique,Diane McKenna-Yasek,Peter C. Sapp,Peter C. Sapp,H R Horvitz,John Landers,John Landers,Robert H. Brown,Robert H. Brown +33 more
TL;DR: Neuronal cytoplasmic protein aggregation and defective RNA metabolism thus appear to be common pathogenic mechanisms involved in ALS and possibly in other neurodegenerative disorders.
Journal ArticleDOI
Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6
Caroline Vance,Boris Rogelj,Tibor Hortobágyi,Kurt J. De Vos,Agnes L. Nishimura,Jemeen Sreedharan,Xun Hu,Bradley N. Smith,Deborah Ruddy,Paul Wright,Jeban Ganesalingam,Kelly L. Williams,Vineeta B. Tripathi,Safa Al-Saraj,Ammar Al-Chalabi,P. Nigel Leigh,Ian P. Blair,Garth A. Nicholson,Garth A. Nicholson,Jackie de Belleroche,Jean-Marc Gallo,Christopher C.J. Miller,Christopher C.J. Miller,Christopher Shaw +23 more
TL;DR: A missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6, is identified, which suggests that a common mechanism may underlie motor neuron degeneration.
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