The RNA Binding Protein TLS Is Translocated to Dendritic Spines by mGluR5 Activation and Regulates Spine Morphology

Fujii, Ritsuko; Okabe, Susumu; Urushido, T.; Inoue, Kiyoshi; Yoshimura, Atsushi; Tachibana, Taro; Nishikawa, Toru; Hicks, Geoffrey; Takumi, Toru

doi:10.1016/j.cub.2005.01.058

Cited by 292 publications

(303 citation statements)

References 26 publications

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“…FUS is found in RNA granules at dendritic spines, and immunodetectable FUS at synapses increases in response to group 1 mGluR stimulation (14,27). Hippocampal cultures from FUS-knockout mice have altered dendritic branching and reduced mature spines (14), suggesting that FUS has an important role at the synapse. We hypothesized that deficits in motor function and sociability in the CAG-FUS R521G "escapers" could be caused by alterations in dendrites or dendritic spines in the motor neurons and/or sensory motor cortex.…”

Section: Altered Dendritic Branching In Spinal Motor Neurons Andmentioning

confidence: 99%

“…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). Moreover, neurons cultured from Significance Both overexpression of wild-type fused in sarcoma (FUS) protein and missense mutations can be pathogenic in a group of related neurodegenerative disorders that includes amyotrophic lateral sclerosis and frontotemporal lobar degeneration.…”

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confidence: 99%

“…FUS-knockout mice have abnormal spine morphology and spine density (14). It is unclear whether pathological FUS mutations disrupt activity-dependent synaptic structure or function.…”

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confidence: 99%

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Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

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

117

116

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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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Section: Altered Dendritic Branching In Spinal Motor Neurons Andmentioning

confidence: 99%

mentioning

confidence: 99%

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Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

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

117

116

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“…In agreement with this, transgenic mice overexpressing wt human FUS were shown to develop ALS with an aggressive phenotype 8 . The findings that both reduced and increased levels of FUS are associated with the ALS phenotype point to the importance of a tight control of FUS expression to ensure correct cellular homeostasis [8][9][10] . Along this line, the identification of mutations affecting the regulation of FUS expression opens interesting new perspectives in the study of FUS regulation in ALS pathogenesis.…”

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confidence: 99%

An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry

et al. 2014

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While the physiologic functions of the RNA-binding protein FUS still await thorough characterization, the pathonegetic role of FUS mutations in amyotrophic lateral sclerosis (ALS) is clearly established. Here we find that a human FUS mutation that leads to increased protein expression, and was identified in two ALS patients with severe outcome, maps to the seed sequence recognized by miR-141 and miR-200a in the 3 0 -UTR of FUS. We demonstrate that FUS and these microRNAs are linked by a feed-forward regulatory loop where FUS upregulates miR-141/200a, which in turn impact FUS protein synthesis. We also show that Zeb1, a target of miR-141/200a and transcriptional repressor of these two microRNAs, is part of the circuitry and reinforces it. Our results reveal a possible correlation between deregulation of this regulatory circuit and ALS pathogenesis, and open interesting perspectives in the treatment of these mutations through ad hoc-modified microRNAs.

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“…Hippocampal neurons from homozygous FUS knock-out mice displayed reduced spine numbers and abnormal dendritic spines as long thin filopodia-like structures. This may be associated with the FUS function in regulating transport of mRNAs encoding actin-stabilizing proteins to maintain the normal dendritic spine morphology [151,152].…”

Section: Rrm-rgg Families: Tdp-43 and Fusmentioning

confidence: 99%

RNA-binding proteins in neurological diseases

Zhou

Mangelsdorf

Liu

et al. 2014

Sci. China Life Sci.

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Emerging studies support that RNA-binding proteins (RBPs) play critical roles in human biology and pathogenesis. RBPs are essential players in RNA processing and metabolism, including pre-mRNA splicing, polyadenylation, transport, surveillance, mRNA localization, mRNA stability control, translational control and editing of various types of RNAs. Aberrant expression of and mutations in RBP genes affect various steps of RNA processing, altering target gene function. RBPs have been associated with various diseases, including neurological diseases. Here, we mainly focus on selected RNA-binding proteins including Nova-1/Nova-2, HuR/HuB/HuC/HuD, TDP-43, Fus, Rbfox1/Rbfox2, QKI and FMRP, discussing their function and roles in human diseases.

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The RNA Binding Protein TLS Is Translocated to Dendritic Spines by mGluR5 Activation and Regulates Spine Morphology

Cited by 292 publications

References 26 publications

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

An ALS-associated mutation in the FUS 3′-UTR disrupts a microRNA–FUS regulatory circuitry

RNA-binding proteins in neurological diseases

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