Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.
Daryl A. Bosco,Nathan Lemay,Hae Kyung Ko,Hongru Zhou,Christopher J. Burke,Thomas J. Kwiatkowski,Peter C. Sapp,Diane McKenna-Yasek,Robert H. Brown,Lawrence J. Hayward +9 more
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TLDR
A novel ALS truncation mutant (R495X) is reported that leads to a relatively severe ALS clinical phenotype compared with FUS missense mutations, and a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS is demonstrated.Abstract:
Mutations in the RNA-binding protein FUS (fused in sarcoma) are linked to amyotrophic lateral sclerosis (ALS), but the mechanism by which these mutants cause motor neuron degeneration is not known. We report a novel ALS truncation mutant (R495X) that leads to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C-terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord caused a striking cytoplasmic accumulation of the protein to a greater extent than that observed for recessive (H517Q) and dominant (R521G) missense mutants. Furthermore, in response to oxidative stress or heat shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wild-type FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. These findings demonstrate a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS.read more
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Journal ArticleDOI
A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation
Avinash Patel,Hyun O. Lee,Louise Jawerth,Shovamayee Maharana,Marcus Jahnel,Marco Y. Hein,Stoyno S. Stoynov,Julia Mahamid,Shambaditya Saha,Titus M. Franzmann,Andrej Pozniakovski,Ina Poser,Nicola Maghelli,Loic Royer,Martin Weigert,Eugene W. Myers,Stephan W. Grill,David N. Drechsel,Anthony A. Hyman,Simon Alberti +19 more
TL;DR: It is proposed that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid- like compartments lie at the heart of ALS and, presumably, other age-related diseases.
Journal ArticleDOI
Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization
Amandine Molliex,Jamshid Temirov,Jihun Lee,Maura Coughlin,Anderson P. Kanagaraj,Hong Joo Kim,Tanja Mittag,J. Paul Taylor +7 more
TL;DR: It is demonstrated that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD), and suggested that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties.
Journal ArticleDOI
Cell-free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers within Hydrogels
Masato Kato,Tina W. Han,Shanhai Xie,Kevin Y. Shi,Xinlin Du,Leeju C. Wu,Hamid Mirzaei,Elizabeth J. Goldsmith,Jamie Longgood,Jimin Pei,Jimin Pei,Nick V. Grishin,Douglas E. Frantz,Jay W. Schneider,She Chen,Lin Li,Michael R. Sawaya,David Eisenberg,Robert Tycko,Steven L. McKnight +19 more
TL;DR: It is discovered that exposure of cell or tissue lysates to a biotinylated isoxazole (b-isox) chemical precipitated hundreds of RNA-binding proteins with significant overlap to the constituents of RNA granules, offering a framework for understanding the function of LC sequences as well as an organizing principle for cellular structures that are not membrane bound.
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
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.
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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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