ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

López-Erauskin, Jone; Tadokoro, Takahiro; Baughn, Michael; Myers, Brian E.; McAlonis-Downes, Melissa; Chillón-Marinas, Carlos; Asiaban, Joshua N.; Artates, Jonathan W.; Bui, Anh Tuan; Vetto, Anne P.; Lee, Sandra K.; Le, Ai Vy; Sun, Yu; Jambeau, Mélanie; Boubaker, J; Swing, Deborah A.; Qiu, Jinsong; Hicks, Geoffrey; Ouyang, Zhengyu; Fu, Xiang‐Dong; Tessarollo, Lino; Ling, Shuo-Chien; Parone, Philippe A.; Shaw, Christopher E.; Maršala, Martin; Lagier‐Tourenne, Clotilde; Cleveland, Don W.; Cruz, Sandrine Da

doi:10.1016/j.neuron.2020.04.006

Cited by 39 publications

(50 citation statements)

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“…Although FUS readily aggregates in the test tube, this is not the case in vivo, and available rodent models expressing mutant FUS do not develop FUS aggregates in the CNS (Devoy et al, 2017;Huang et al, 2011;Ló pez-Erauskin et al, 2018;Scekic-Zahirovic et al, 2016;Sharma et al, 2016). Our studies showed that to achieve efficient FUS aggregation in the murine nervous system, highly aggregate-prone artificial variants of FUS lacking RNA binding domains have to be used (Robinson et al, 2015;Shelkovnikova et al, 2013a).…”

Section: Introductionmentioning

confidence: 85%

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Shelkovnikova

Skelt

et al. 2019

Cell Reports

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Section: Introductionmentioning

confidence: 85%

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Shelkovnikova

Skelt

et al. 2019

Cell Reports

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“…Two reports have recently shown that mutant FUS overexpression can impair protein synthesis in neurons (López-Erauskin et al, 2018;Murakami et al, 2015), but whether this also occurs with physiological FUS expression is not currently known. In order to investigate this, we used the ∆14 FUS knock-in mouse model (Devoy et al, 2017), in which a mutation causing aggressive and early-onset ALS (DeJesus-Hernandez et al, 2010), leads to skipping of exon 14 and a frameshift in exon 15.…”

Section: Cytoplasmic Fus Represses Translationmentioning

confidence: 99%

“…The role of FUS in the cytoplasm and the functional consequences of ALS-linked mutations are poorly understood. In addition to a role in stress response, it was recently observed that, in transgenic and overexpression models, mutant FUS was associated with an impairment in protein translation (Kamelgarn et al, 2018;López-Erauskin et al, 2018;Murakami et al, 2015). Further, an increasing number of studies suggests that FUS liquid-liquid phase separation (LLPS) properties play a crucial role in its cytoplasmic gain of function.…”

Section: Introductionmentioning

confidence: 99%

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

Birsa

Ule

Garone

et al. 2020

Preprint

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Mutations in the RNA binding protein (RBP) FUS cause amyotrophic lateral sclerosis (ALS) and result in its nuclear depletion and cytoplasmic mislocalisation, with cytoplasmic gain of function thought to be crucial in pathogenesis. Here, we show that expression of mutant FUS at physiological levels drives translation inhibition in both mouse and human motor neurons. Rather than acting directly on the translation machinery, we find that mutant FUS forms cytoplasmic condensates that promote the phase separation of FMRP, another RBP associated with neurodegeneration and robustly involved in translation regulation. FUS and FMRP co-partition and repress translation in vitro. In our in vivo model, FMRP RNA targets are depleted from ribosomes. Our results identify a novel paradigm by which FUS mutations favour the condensed state of other RBPs, impacting on crucial biological functions, such as protein translation.

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“…Mutations of FUS gene were thought to cause synaptic dysfunction and pathological protein aggregation, which were felt to be key events leading to neuronal degeneration . However, the most recent studies have revealed that the expression of mutant FUS leads to stress‐mediated induction of chaperones, decreased expression of ion channels and transporters essential for synaptic function, and reduced synaptic activity without the loss of nuclear FUS or its cytoplasmic aggregation . The nuclear effects of FUS also seem to result in impairment of the function of paraspeckles, granules in the nuclear interchromatin space that are assembled on a scaffold long noncoding RNA (lncRNA) NEAT1 .…”

Section: Introductionmentioning

confidence: 99%

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

et al. 2019

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Aims:Mutations in DNA/RNA-binding factor (fused-in-sarcoma) FUS and superoxide dismutase-1 (SOD-1) cause amyotrophic lateral sclerosis (ALS). They were reproduced in SOD-1-G93A (SOD-1) and new FUS[1-359]-transgenic (FUS-tg) mice, where inflammation contributes to disease progression. The effects of standard disease therapy and anti-inflammatory treatments were investigated using these mutants. Methods: FUS-tg mice or controls received either vehicle, or standard ALS treatment riluzole (8 mg/kg/day), or anti-inflammatory drug a selective blocker of cyclooxygenase-2 celecoxib (30 mg/kg/day) for six weeks, or a single intracerebroventricular (i.c.v.) infusion of Neuro-Cells (a preparation of 1.39 × 10 6 mesenchymal and hemopoietic human stem cells, containing 5 × 10 5 of CD34 + cells), which showed antiinflammatory properties. SOD-1 mice received i.c.v.-administration of Neuro-Cells or vehicle.Results: All FUS-tg-treated animals displayed less marked reductions in weight gain, food/water intake, and motor deficits than FUS-tg-vehicle-treated mice. Neuro-Celltreated mutants had reduced muscle atrophy and lumbar motor neuron degeneration.This group but not celecoxib-FUS-tg-treated mice had ameliorated motor performance and lumbar expression of microglial activation marker, ionized calcium-binding adapter molecule-1 (Iba-1), and glycogen-synthase-kinase-3ß (GSK-3ß). The Neuro-Cells-treated-SOD-1 mice showed better motor functions than vehicle-treated-SOD-1 group. Conclusion:The neuropathology in FUS-tg mice is sensitive to standard ALS treatments and Neuro-Cells infusion. The latter improves motor outcomes in two ALS models possibly by suppressing microglial activation. | 505MUNTER ET al.

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ALS/FTD-Linked Mutation in FUS Suppresses Intra-axonal Protein Synthesis and Drives Disease Without Nuclear Loss-of-Function of FUS

Cited by 39 publications

References 0 publications

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

FUS-ALS mutants alter FMRP phase separation equilibrium and impair protein translation

Neuro‐Cells therapy improves motor outcomes and suppresses inflammation during experimental syndrome of amyotrophic lateral sclerosis in mice

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