Requirements for Stress Granule Recruitment of Fused in Sarcoma (FUS) and TAR DNA-binding Protein of 43 kDa (TDP-43)

Bentmann, Eva; Neumann, Manuela; Tahirović, Sabina; Rodde, Ramona; Dormann, Dorothee; Haass, Christian

doi:10.1074/jbc.m111.328757

Cited by 250 publications

(314 citation statements)

References 76 publications

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“…In response to various stressors, FUS localizes into cytoplasmic stress granules (13). In neurons, there is more immunodetectable FUS at dendritic spines in response to metabolic glutamate receptor (mGluR) agonists (14).…”

mentioning

confidence: 99%

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

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

126

123

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The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS WT ) and a pathological mutation (FUS R521G A myotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 3-5 y of onset. Interestingly, ∼10-15% of ALS patients have clinical features of frontotemporal lobar degeneration (FTLD), marked by a decline in decision-making, behavioral control, emotion, and language, and as many as half have mild-to-moderate cognitive or behavioral abnormalities (1). FTLD comprises a group of heterogeneous diseases characterized by progressive neurodegeneration of the frontal and temporal lobes and clinically by frontotemporal dementia (FTD) with or without motor neuron disease. There is no cure or effective therapy for those who suffer from ALS or FTLD, and the mechanisms by which these diseases occur are not well understood.The clinical, pathological, and genetic overlap between ALS and FTLD suggests that there are mechanisms shared by these diseases. The RNA-binding proteins fused in sarcoma (FUS) and transactive response DNA-binding protein-43 (TDP-43) are the major protein components of inclusions that are characteristic of ALS and FTLD-U (FTLD with ubiquitinated inclusions) (2). More than 50 genetic FUS mutations have been identified in these related neurodegenerative disorders (3). Similarly, more than 40 dominant mutations in the TDP-43 gene have been linked to ALS cases and, to a lesser extent, to FTLD (4). The identification of mutations in the FUS and TDP-43 genes has provided insights for uncovering the disease mechanisms for ALS and FTLD.FUS is a ubiquitously expressed RNA-binding protein that exists in dynamic ribonucleoprotein complexes involved in pre-mRNA splicing, mRNA stability, and mRNA transport. FUS is a member of the FET family of proteins that bind RNAs (5) and contains an RNA recognition motif, three arginine-glycine-glycine (RGG) boxes, and a zinc finger (ZnF) (6). RGG2-ZnF-RGG3 is the major RNA-binding domain, which has a preference for GUrich sequences (7,8). The N terminus of FUS contains a lowcomplexity sequence domain involved in RNA granule formation (9). Nucleocytoplasmic shuttling of FUS occurs by a nonclassical proline-tyrosine nuclear localization signal (PY-NLS) and a nuclear export signal (NES) (10). Methylation of the C-terminal RGG3 domain of FUS is necessary for transportin 1 interaction and nuclear localization (11).The majority of clinical ALS/FTLD-associated FUS mutations occur in its C-terminal PY-NLS seque...

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mentioning

confidence: 99%

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

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

126

123

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“…However, whether this reflects reduced function of the mutated proteins, a toxic gain of function, or both is not known (Mackenzie and Neumann 2012). In FUS cases, FUS-containing cytoplasmic aggregates are observed in patient spinal cord motor neurons and ex vivo fibroblasts (Munoz et al 2009;Neumann et al 2009;Vance et al 2013), similar to aggregates detected with TDP-43 mutant proteins (Bentmann et al 2012). How such aggregates might contribute to ALS is unknown.…”

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confidence: 99%

ALS mutations in TLS/FUS disrupt target gene expression

Coady

Manley

2015

Genes Dev.

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Amyotrophic lateral sclerosis (ALS) is caused by mutations in a number of genes, including the gene encoding the RNA/DNA-binding protein translocated in liposarcoma or fused in sarcoma (TLS/FUS or FUS). Previously, we identified a number of FUS target genes, among them MECP2. To investigate how ALS mutations in FUS might impact target gene expression, we examined the effects of several FUS derivatives harboring ALS mutations, such as R521C (FUS C ), on MECP2 expression in transfected human U87 cells. Strikingly, FUS C and other mutants not only altered MECP2 alternative splicing but also markedly increased mRNA abundance, which we show resulted from sharply elevated stability. Paradoxically, however, MeCP2 protein levels were significantly reduced in cells expressing ALS mutant derivatives. Providing a parsimonious explanation for these results, biochemical fractionation and in vivo localization studies revealed that MECP2 mRNA colocalized with cytoplasmic FUS C in insoluble aggregates, which are characteristic of ALS mutant proteins. Together, our results establish that ALS mutations in FUS can strongly impact target gene expression, reflecting a dominant effect of FUS-containing aggregates.

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“…Deletion of the RNA-binding domains in TDP43 and FUS both prevents their inclusion in stress granules and reduces their toxicity [34,[39][40][41]. Moreover, components of stress granules have been detected in TDP43-rich cytoplasmic deposits in spinal neurons of patients with ALS [56,99,101], but are less common in cortical neurons [102]. These results may be explained by the preferential accumulation of fulllength TDP43 in spinal neurons of patients with ALS, in contrast to the deposition of carboxy-terminal fragments of TDP43 in cortical neurons [103].…”

Section: Rna Granulesmentioning

confidence: 99%

“…These results may be explained by the preferential accumulation of fulllength TDP43 in spinal neurons of patients with ALS, in contrast to the deposition of carboxy-terminal fragments of TDP43 in cortical neurons [103]. Such fragments lack the first RNA recognition motif (RRM1), as well as a portion of the prion-like domain, both of which are required for stress granule formation [102].…”

Section: Rna Granulesmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

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The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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Requirements for Stress Granule Recruitment of Fused in Sarcoma (FUS) and TAR DNA-binding Protein of 43 kDa (TDP-43)

Cited by 250 publications

References 76 publications

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

ALS mutations in TLS/FUS disrupt target gene expression

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

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