Role of FET proteins in neurodegenerative disorders

Svetoni, Francesca; Frisone, Paola; Paronetto, Maria Paola

doi:10.1080/15476286.2016.1211225

Cited by 81 publications

(86 citation statements)

References 146 publications

(127 reference statements)

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“…1; Rowland and Shneider 2001). Second, ALS primarily affects adults, with an average age at onset of 60 yr (Svetoni et al 2016), although, in some more aggressive forms of disease, patients are afflicted in early adulthood or adolescence (Swinnen and Robberecht 2014). Third, ALS is nearly always fatal, usually after an average disease duration of 3-5 yr (Rowland and Shneider 2001), while patients with less severe forms of SMA have normal life spans (Zerres et al 1997).…”

Section: Alsmentioning

confidence: 99%

“…However, unlike with TDP-43, FUS pathology never presents without FUS mutations, >50 of which have been described (Nolan et al 2016). Whereas disease-causing TDP-43 mutations are clustered in the C-terminal G-rich and Q/N regions, FUS mutations occur throughout the protein, although the most common and well-described are in the C-terminal NLS (Shang and Huang 2016;Svetoni et al 2016). Such mutations have been proposed to influence the cytoplasmic aggregation and nuclear clearance of the protein.…”

Section: Fusmentioning

confidence: 99%

See 1 more Smart Citation

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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Neurodegeneration is a leading cause of death in the developed world and a natural, albeit unfortunate, consequence of longer-lived populations. Despite great demand for therapeutic intervention, it is often the case that these diseases are insufficiently understood at the basic molecular level. What little is known has prompted much hopeful speculation about a generalized mechanistic thread that ties these disparate conditions together at the subcellular level and can be exploited for broad curative benefit. In this review, we discuss a prominent theory supported by genetic and pathological changes in an array of neurodegenerative diseases: that neurons are particularly vulnerable to disruption of RNA-binding protein dosage and dynamics. Here we synthesize the progress made at the clinical, genetic, and biophysical levels and conclude that this perspective offers the most parsimonious explanation for these mysterious diseases. Where appropriate, we highlight the reciprocal benefits of cross-disciplinary collaboration between disease specialists and RNA biologists as we envision a future in which neurodegeneration declines and our understanding of the broad importance of RNA processing deepens.

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Section: Alsmentioning

confidence: 99%

Section: Fusmentioning

confidence: 99%

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

2017

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“…The other members of the FET family, TAF15 and EWS, can also be found in these inclusions, and strikingly their nuclear import receptor transportin‐1; the presence of these additional proteins and hypomethylation of FUS distinguishes FTLD‐FUS from ALS‐linked FUS only pathology . Like TDP‐43, FUS and the other FET proteins are RNA‐binding proteins with a predominant function in RNA metabolism and transport . Three very rare cases of FTD with FUS mutation (one FTD, two FTD‐ALS) have been reported .…”

Section: Modelling Ftd Pathology Directlymentioning

confidence: 99%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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“…FET proteins comprise a family of highly conserved predominantly nuclear proteins that include fused in sarcoma (FUS), EWS and TAF15. These proteins are ubiquitously expressed and involved in regulation of gene expression, as well as in RNA processing, transport and metabolism …”

Section: Introductionmentioning

confidence: 99%

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Lysikova

Kukharsky

Chaprov

et al. 2019

Genes Brain and Behavior

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Multiple clinical and experimental evidences suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are members of a disease continuum. Pathological inclusions of fused in sarcoma (FUS) protein have been observed in subsets of patients with these diseases but their anatomical distribution is different for two diseases. These structures are present in motor neurons in ALS cases but in cortical neurons in FTLD cases. Expression of a C‐terminally truncated form of human FUS causes an early onset and progressive motor neuron pathology in transgenic mice but only when these neurons express a certain level of this protein. Severe motor dysfunction and early lethality of mice with expression above this level prevent their use for studies of FTLD‐related pathology caused by expression of this form of FUS. In the present study, we used another line of mice expressing the same protein but not developing any signs of motor system dysfunction due to substantially lower level of transgene expression in motor neurons. In a set of tests 5‐month old mice displayed certain behavioural abnormalities, including increased impulsivity, decreased anxiety and compromised social interaction, which recapitulate behaviour characteristics typically seen in FTLD patients.

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Role of FET proteins in neurodegenerative disorders

Cited by 81 publications

References 146 publications

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

RNA-binding proteins in neurodegeneration: mechanisms in aggregate

Review: Modelling the pathology and behaviour of frontotemporal dementia

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

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