ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import
Dorothee Dormann,Dorothee Dormann,Ramona Rodde,Ramona Rodde,Dieter Edbauer,Eva Bentmann,Eva Bentmann,Ingeborg Fischer,Alexander Hruscha,Manuel E Than,Ian R. A. Mackenzie,Anja Capell,Anja Capell,Bettina Schmid,Manuela Neumann,Christian Haass,Christian Haass +16 more
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TLDR
It is proposed that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS‐opathies.Abstract:
Mutations in fused in sarcoma (FUS) are a cause of familial amyotrophic lateral sclerosis (fALS). Patients carrying point mutations in the C-terminus of FUS show neuronal cytoplasmic FUS-positive inclusions, whereas in healthy controls, FUS is predominantly nuclear. Cytoplasmic FUS inclusions have also been identified in a subset of frontotemporal lobar degeneration (FTLD-FUS). We show that a non-classical PY nuclear localization signal (NLS) in the C-terminus of FUS is necessary for nuclear import. The majority of fALS-associated mutations occur within the NLS and impair nuclear import to a degree that correlates with the age of disease onset. This presents the first case of disease-causing mutations within a PY-NLS. Nuclear import of FUS is dependent on Transportin, and interference with this transport pathway leads to cytoplasmic redistribution and recruitment of FUS into stress granules. Moreover, proteins known to be stress granule markers co-deposit with inclusions in fALS and FTLD-FUS patients, implicating stress granule formation in the pathogenesis of these diseases. We propose that two pathological hits, namely nuclear import defects and cellular stress, are involved in the pathogenesis of FUS-opathies.read more
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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.
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The changing scene of amyotrophic lateral sclerosis
TL;DR: New findings in ALS research are summarized, what they have taught us about this disease are discussed and issues that are still outstanding are examined.
Journal ArticleDOI
TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia
TL;DR: 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.
Journal ArticleDOI
RNA buffers the phase separation behavior of prion-like RNA binding proteins
Shovamayee Maharana,Jie Wang,Dimitrios K. Papadopoulos,Dimitrios K. Papadopoulos,Doris Richter,Andrey Pozniakovsky,Ina Poser,Marc Bickle,Sandra Rizk,Sandra Rizk,Jordina Guillén-Boixet,Titus M. Franzmann,Marcus Jahnel,Marcus Jahnel,Lara Marrone,Young-Tae Chang,Jared Sterneckert,Pavel Tomancak,Anthony A. Hyman,Simon Alberti +19 more
TL;DR: It is proposed that the nucleus is a buffered system in which high RNA concentrations keep RBPs soluble, and low RNA/protein ratios promote phase separation into liquid droplets, whereas high ratios prevent droplet formation in vitro.
Journal ArticleDOI
Stress granules as crucibles of ALS pathogenesis
TL;DR: This work has shown that TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate, critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis.
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
A short amino acid sequence able to specify nuclear location
TL;DR: By reducing the size of the transposed sequence, it is concluded that Pro-Lys- lys- Lys-Arg-L Lys-Val can act as a nuclear location signal and may represent a prototype of similar sequences in other nuclear proteins.
Journal ArticleDOI
Accurate Bond and Angle Parameters for X-ray Protein Structure Refinement
Richard A. Engh,Robert Huber +1 more
TL;DR: In this article, a statistical survey of X-ray structures of small compounds from the Cambridge Structural Database is used for the refinement of protein structures determined by X-Ray crystallography.
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.
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