The role of FUS gene variants in neurodegenerative diseases

Deng, Hao; Gao, Kai; Jankovic, Joseph

doi:10.1038/nrneurol.2014.78

Cited by 290 publications

(276 citation statements)

References 203 publications

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“…Considering that transcription-coupled splicing is such a fundamental cellular process, it is possible that its disruption by mutant FUS contributes to the pathogenesis of ALS. In support of this possibility, many of the mutations in FUS that are ALScausative are located in the nuclear localization signal (NLS), which leads to mislocalization of FUS to the cytoplasm in ALS patient cells (29,38,39). Moreover, we recently obtained evidence that the U1 snRNP core complex (U1 snRNA and the Sm proteins) is comislocalized to the cytoplasm with FUS in ALS patient fibroblasts harboring mutations in the NLS (40).…”

Section: Fus Is Required For the Interaction Between Rnap II And U1 Smentioning

confidence: 88%

“…Moreover, we recently obtained evidence that the U1 snRNP core complex (U1 snRNA and the Sm proteins) is comislocalized to the cytoplasm with FUS in ALS patient fibroblasts harboring mutations in the NLS (40). Thus, decreased levels of both FUS and U1 snRNP in the nucleus may lead to the aberrant splicing that has been reported in transfected cells and ALS patient cells expressing FUS with NLS mutations (29,30,38,39). In previous work, FUS was shown to bind to the C-terminal domain of RNAP II and regulate phosphorylation of serine-2 (23,25,27).…”

Section: Fus Is Required For the Interaction Between Rnap II And U1 Smentioning

confidence: 98%

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FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

Reed

2015

Proc. Natl. Acad. Sci. U.S.A.

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Pre-mRNA splicing is coupled to transcription by RNA polymerase II (RNAP II). We previously showed that U1 small nuclear ribonucleoprotein (snRNP) associates with RNAP II, and both RNAP II and U1 snRNP are also the most abundant factors associated with the protein fused-in-sarcoma (FUS), which is mutated to cause the neurodegenerative disease amyotrophic lateral sclerosis. Here, we show that an antisense morpholino that base-pairs to the 5′ end of U1 snRNA blocks splicing in the coupled system and completely disrupts the association between U1 snRNP and both FUS and RNAP II, but has no effect on the association between FUS and RNAP II. Conversely, we found that U1 snRNP does not interact with RNAP II in FUS knockdown extracts. Moreover, using these extracts, we found that FUS must be present during the transcription reaction in order for splicing to occur. Together, our data lead to a model that FUS functions in coupling transcription to splicing via mediating an interaction between RNAP II and U1 snRNP.ALS | coupling transcription to splicing | RNA polymerase II | U1 snRNP I t is now well established that the steps in gene expression are extensively coupled to one another, including both physical and functional coupling between RNA polymerase II (RNAP II) transcription and pre-mRNA processing (1-11). Moreover, the majority of nascent transcripts are spliced cotranscriptionally, while the transcripts are still tethered to RNAP II. In vitro systems have been developed for the coupled transcription/splicing (txn/splicing) reaction as well as for cotranscriptional splicing, and these systems have been used to investigate the mechanisms underlying these processes (12-17). In the case of coupled txn/ splicing, studies using the in vitro system revealed that transcription potently enhances spliceosome assembly, which in turn leads to a strong enhancement of the splicing reaction (13). Additional studies revealed that the only essential splicing factors that copurify with RNAP II are U1 small nuclear ribonucleoprotein (snRNP) and its associated factors, the serine/ arginine-rich (SR) proteins (18)(19)(20). This observation is particularly noteworthy because U1 snRNP/SR proteins are the first splicing factors that bind to pre-mRNA during spliceosome assembly (21). Although functional studies indicate that SR proteins play a key role in coupling transcription to splicing (19), the role of U1 snRNP in this coupling event has not been examined. It is also not known how U1 snRNP interacts with RNAP II. U1 snRNA is known to base-pair to the 5′ splice site during the earliest steps in spliceosome assembly, and this interaction is essential for splice-site recognition (21). In addition, we and others found that U1 snRNP/SR and RNAP II are among the main factors that associate with the protein fused-in-sarcoma (FUS) (19,(22)(23)(24)(25)(26)(27). Understanding the normal roles of FUS and the pathways in which it functions are of great importance because FUS is mutated to cause the fatal motor neuron disease amyotrophic lateral s...

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Section: Fus Is Required For the Interaction Between Rnap II And U1 Smentioning

confidence: 88%

Section: Fus Is Required For the Interaction Between Rnap II And U1 Smentioning

confidence: 98%

FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

Reed

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…The OPA1 gene, which encodes a mitochondrial GTPase, was initially identified as the gene mutated in an inherited form of blindness, although this gene has subsequently also been linked to diabetes and "multiple system disease" (61). Finally, both the amyloid precursor protein APP and the RNA-binding protein FUS are well documented to be involved in multiple neuropathologies, including Alzheimer's disease and amyotrophic lateral sclerosis (62,63). Although further work remains to define the precise phenotypic effects of CELF2-regulated alternative splicing events on thymocyte development, the data we present here clearly demonstrate the biologic importance of CELF2 outside of the neuromuscular system, and identify new targets and mechanisms of CELF2 regulation that likely have broad impact across all tissues in which this ubiquitous protein is expressed.…”

Section: Discussionmentioning

confidence: 99%

Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling

Mallory

Allon

Qiu

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Studies in several cell types have highlighted dramatic and diverse changes in mRNA processing that occur upon cellular stimulation. However, the mechanisms and pathways that lead to regulated changes in mRNA processing remain poorly understood. Here we demonstrate that expression of the splicing factor CELF2 (CUGBP, Elav-like family member 2) is regulated in response to T-cell signaling through combined increases in transcription and mRNA stability. Transcriptional induction occurs within 6 h of stimulation and is dependent on activation of NF-κB. Subsequently, there is an increase in the stability of the CELF2 mRNA that correlates with a change in CELF2 3′UTR length and contributes to the total signalinduced enhancement of CELF2 expression. Importantly, we uncover dozens of splicing events in cultured T cells whose changes upon stimulation are dependent on CELF2 expression, and provide evidence that CELF2 controls a similar proportion of splicing events during human thymic T-cell development. Taken together, these findings expand the physiologic impact of CELF2 beyond that previously documented in developing neuronal and muscle cells to T-cell development and function, identify unappreciated instances of alternative splicing in the human thymus, and uncover novel mechanisms for CELF2 regulation that may broadly impact CELF2 expression across diverse cell types.alternative splicing | CELF2 | thymic development | T cells | mRNA stability

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“…It is enriched in the nucleus and involved in transcription, DNA repair, and RNA biogenesis (Polymenidou et al, 2012;Wang et al, 2008Wang et al, , 2013. Mutations in FUS are associated with amyotrophic lateral sclerosis (ALS) and rare forms of frontotemporal lobar degeneration (FTLD) (Deng et al, 2014;Woulfe et al, 2010). Recent reports show that the prion-like LC domains of FUS can polymerize into fibrous amyloid-like assemblies in a cellfree system Kato et al, 2012;Kwon et al, 2013Kwon et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation

Patel

Lee

Jawerth

et al. 2015

Cell

2,425

147

3,091

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Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose 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.

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The role of FUS gene variants in neurodegenerative diseases

Cited by 290 publications

References 203 publications

FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

FUS functions in coupling transcription to splicing by mediating an interaction between RNAP II and U1 snRNP

Induced transcription and stability of CELF2 mRNA drives widespread alternative splicing during T-cell signaling

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation

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