FUS/TLS-immunoreactive Neuronal and Glial Cell Inclusions Increase With Disease Duration in Familial Amyotrophic Lateral Sclerosis With an R521C<i>FUS/TLS</i>Mutation

Suzuki, Naoki; Kato, Shinsuke; Kato, Masako; Warita, Hitoshi; Mizuno, Hideki; Kato, Masaaki; Shimakura, N.; Akiyama, Haruhiko; Kobayashi, Zen; Konno, Hidehiko; Akiyama, Masashi

doi:10.1097/nen.0b013e318264f164

Cited by 38 publications

(26 citation statements)

References 35 publications

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“…Moreover, FUS cytoplasmic aggregates have been observed in oligodendrocytes of ALS- FUS patients [51, 77] as well as in FTD patients with FUS pathology [58]. In non- FUS ALS patients, myelin loss has been observed in sporadic ALS patients and inclusions of TDP-43 are frequent in oligodendrocytes [41, 63].…”

Section: Discussionmentioning

confidence: 99%

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

et al. 2017

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Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1687-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

et al. 2017

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“…Our observation that endogenous wildtype FUS protein was co-localized with the cytoplasmic aggregates of FUS mutants in both HEK293 cells and NSC-34 motor neuron cells suggests that the FUS mutants may further sequester the wildtype FUS protein in the cytoplasm and form more aggregates. In ALS, FUS cytoplasmic accumulation is a progressive process and increases with disease duration [58]. The deficient FUS autoregulation may lead to long term detrimental effects, and could be part of the mechanism underlying age-dependent neurodegeneration and death of neurons with ALS-associated FUS mutants.…”

Section: Discussionmentioning

confidence: 99%

ALS-Associated FUS Mutations Result in Compromised FUS Alternative Splicing and Autoregulation

et al. 2013

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The gene encoding a DNA/RNA binding protein FUS/TLS is frequently mutated in amyotrophic lateral sclerosis (ALS). Mutations commonly affect its carboxy-terminal nuclear localization signal, resulting in varying deficiencies of FUS nuclear localization and abnormal cytoplasmic accumulation. Increasing evidence suggests deficiencies in FUS nuclear function may contribute to neuron degeneration. Here we report a novel FUS autoregulatory mechanism and its deficiency in ALS-associated mutants. Using FUS CLIP-seq, we identified significant FUS binding to a highly conserved region of exon 7 and the flanking introns of its own pre-mRNAs. We demonstrated that FUS is a repressor of exon 7 splicing and that the exon 7-skipped splice variant is subject to nonsense-mediated decay (NMD). Overexpression of FUS led to the repression of exon 7 splicing and a reduction of endogenous FUS protein. Conversely, the repression of exon 7 was reduced by knockdown of FUS protein, and moreover, it was rescued by expression of EGFP-FUS. This dynamic regulation of alternative splicing describes a novel mechanism of FUS autoregulation. Given that ALS-associated FUS mutants are deficient in nuclear localization, we examined whether cells expressing these mutants would be deficient in repressing exon 7 splicing. We showed that FUS harbouring R521G, R522G or ΔExon15 mutation (minor, moderate or severe cytoplasmic localization, respectively) directly correlated with respectively increasing deficiencies in both exon 7 repression and autoregulation of its own protein levels. These data suggest that compromised FUS autoregulation can directly exacerbate the pathogenic accumulation of cytoplasmic FUS protein in ALS. We showed that exon 7 skipping can be induced by antisense oligonucleotides targeting its flanking splice sites, indicating the potential to alleviate abnormal cytoplasmic FUS accumulation in ALS. Taken together, FUS autoregulation by alternative splicing provides insight into a molecular mechanism by which FUS-regulated pre-mRNA processing can impact a significant number of targets important to neurodegeneration.

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“…In healthy controls this multifunctional protein, with roles ranging from DNA repair, transcriptional regulation and mRNA transport (Lagier-Tourenne, Polymenidou, & Cleveland, 2010), is located primarily in the nucleus (Dormann et al, 2010); however, post mortem tissues of FUS-ALS patients reveal cytoplasmic inclusions in affected neurons and glia (Kwiatkowski et al, 2009). Specifically, carriers of the FUS R521C, R521G, R521H, R524W, or G507N mutations show wide-spread FUS pathology (Blair et al, 2009;Hewitt et al, 2010;Rademakers et al, 2010), including glial and neuronal cell loss, with increasing distribution of FUS-immunoreactive inclusions in patients with longer disease durations (Suzuki et al, 2012). Carriers of FUS R521C mutation also show numerous oligodendroglial cytoplasmic inclusions (Mackenzie et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

Kia

McAvoy

Krishnamurthy

et al. 2018

Glia

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Mutations in fused in sarcoma (FUS) are linked to amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease affecting both upper and lower motor neurons. While it is established that astrocytes contribute to the death of motor neurons in ALS, the specific contribution of mutant FUS (mutFUS) through astrocytes has not yet been studied. Here, we used primary astrocytes expressing a N‐terminally GFP tagged R521G mutant or wild‐type FUS (WTFUS) and show that mutFUS‐expressing astrocytes undergo astrogliosis, damage co‐cultured motor neurons via activation of an inflammatory response and produce conditioned medium (ACM) that is toxic to motor neurons in isolation. Time lapse imaging shows that motor neuron cultures exposed to mutFUS ACM, but not WTFUS ACM, undergo significant cell loss, which is preceded by progressive degeneration of neurites. We found that Tumor Necrosis Factor‐Alpha (TNFα) is secreted into ACM of mutFUS‐expressing astrocytes. Accordingly, mutFUS astrocyte‐mediated motor neuron toxicity is blocked by targeting soluble TNFα with neutralizing antibodies. We also found that mutant astrocytes trigger changes to motor neuron AMPA receptors (AMPAR) that render them susceptible to excitotoxicity and AMPAR‐mediated cell death. Our data provide the first evidence of astrocytic involvement in FUS‐ALS, identify TNFα as a mediator of this toxicity, and provide several potential therapeutic targets to protect motor neurons in FUS‐linked ALS.

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FUS/TLS-immunoreactive Neuronal and Glial Cell Inclusions Increase With Disease Duration in Familial Amyotrophic Lateral Sclerosis With an R521CFUS/TLSMutation

Cited by 38 publications

References 35 publications

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

ALS-Associated FUS Mutations Result in Compromised FUS Alternative Splicing and Autoregulation

Astrocytes expressing ALS‐linked mutant FUS induce motor neuron death through release of tumor necrosis factor‐alpha

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