FUS/TLS forms cytoplasmic aggregates, inhibits cell growth and interacts with TDP-43 in a yeast model of amyotrophic lateral sclerosis

Laboratory of Biochemistry and Genetics, National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Protein & Cell (Impact Factor: 2.85). 03/2011; 2(3):223-36. DOI: 10.1007/s13238-011-1525-0
Source: PubMed

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by the premature loss of motor neurons. While the underlying cellular mechanisms of neuron degeneration are unknown, the cytoplasmic aggregation of several proteins is associated with sporadic and familial forms of the disease. Both wild-type and mutant forms of the RNA-binding proteins FUS and TDP-43 accumulate in cytoplasmic inclusions in the neurons of ALS patients. It is not known if these so-called proteinopathies are due to a loss of function or a gain of toxicity resulting from the formation of cytoplasmic aggregates. Here we present a model of FUS toxicity using the yeast Saccharomyces cerevisiae in which toxicity is associated with greater expression and accumulation of FUS in cytoplasmic aggregates. We find that FUS and TDP-43 have a high propensity for co-aggregation, unlike the aggregation patterns of several other aggregation-prone proteins. Moreover, the biophysical properties of FUS aggregates in yeast are distinctly different from many amyloidogenic proteins, suggesting they are not composed of amyloid.

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Available from: Dmitry Kryndushkin, Feb 03, 2014
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    • "This would be consistent with a model where either mutation of the protein or differential regulation of the gene transcription or translation could lead to dysregulation of gene networks or pathway. For example, both the mutant forms of FUS or excessive amounts of normal FUS protein lead to perturbed localization of FUS in the cytoplasm rather than in the nucleus of the cell (Mitchell et al., 2013; Gal et al., 2011; Ito et al., 2011; Kryndushkin et al., 2011). Mutant FUS is located in stress granules while wild type FUS forms globular and skein-like inclusions. "
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    ABSTRACT: Fused-In-Sarcoma (FUS) is a candidate gene for neurological disorders including motor neurone disease and Parkinson׳s disease in addition to various types of cancer. Recently it has been reported that over expression of FUS causes motor neurone disease in mouse models hence mutations leading to changes in gene expression may contribute to the development of neurodegenerative disease. Genome evolutionary conservation was used to predict important cis-acting DNA regulators of the FUS gene promoter that direct transcription. The putative regulators identified were analysed in reporter gene assays in cells and in chick embryos. Our analysis indicated in addition to regulatory domains 5′ of the transcriptional start site an important regulatory domain resides in intron 1 of the gene itself. This intronic domain functioned both in cell lines and in vivo in the neural tube of the chick embryo including developing motor neurones. Our data suggest the interaction of multiple domains including intronic domains are involved in expression of FUS. A better understanding of the regulation of expression of FUS may give insight into how its stimulus inducible expression may be associated with neurological disorders.
    Brain Research 11/2014; 1595. DOI:10.1016/j.brainres.2014.10.056 · 2.83 Impact Factor
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    • "Cytosolic mislocalization and deposition of the FET proteins may also create a toxic 'gain-of-function', e.g. through aberrant binding of cytosolic RNA targets (Hoell et al., 2011) or altered protein–protein interactions. Overexpression of FUS or mutant FUS in yeast and various model animals indeed causes toxicity and recapitulates certain disease features (Chen et al., 2011; Fushimi et al., 2011; Huang et al., 2011; Ju et al., 2011; Kabashi et al., 2011; Kryndushkin et al., 2011; Lanson et al., 2011; Murakami et al., 2012; Sun et al., 2011; Vaccaro et al., 2012; Verbeeck et al., 2012). However under physiological conditions, FUS levels appear to be tightly regulated by an autoregulatory mechanism (Lagier-Tourenne et al., 2012), suggesting that overexpression models should be interpreted with caution. "
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    ABSTRACT: Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients. Moreover, FUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of FUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family.
    Molecular and Cellular Neuroscience 04/2013; 56. DOI:10.1016/j.mcn.2013.03.006 · 3.73 Impact Factor
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    • "In yeast, FUS and TDP-43 have a high propensity of co-aggregation that is not seen with other aggregate-prone proteins (Kryndushkin et al., 2011). In Drosophila, FUS expression drives a neurodegenerative eye phenotype that is enhanced by co-expression of normal human or mutant TDP-43 (Lanson et al., 2011). "
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    ABSTRACT: The expression, processing, transport and activities of both coding and non-coding RNAs play critical roles in normal neuronal function and differentiation. Over the past decade, these same pathways have come under scrutiny as potential contributors to neurodegenerative disease. Here we focus broadly on the roles of RNA and RNA processing in neurodegeneration. We first discuss a set of "RNAopathies", where non-coding repeat expansions drive pathogenesis through a surprisingly diverse set of mechanisms. We next explore an emerging class of "RNA binding proteinopathies" where redistribution and aggregation of the RNA binding proteins TDP-43 or FUS contribute to a potentially broad range of neurodegenerative disorders. Lastly, we delve into the potential contributions of alterations in both short and long non-coding RNAs to neurodegenerative illness.
    Progress in Neurobiology 11/2011; 97(2):173-89. DOI:10.1016/j.pneurobio.2011.10.006 · 10.30 Impact Factor
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