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: 3.25). 03/2011; 2(3):223-36. DOI: 10.1007/s13238-011-1525-0
Source: PubMed


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 · 2.84 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 · 3.84 Impact Factor
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    • "ALS-linked TDP-43 mutations increase protein stability and increase its association with FUS [189]. A complex of the two proteins inhibits cell growth in yeast [190] and impacts movement and lifespan in Drosophila [191], effects possibly mediated by co-regulation of histone deacetylase 6 (HDAC6) mRNA [192]. "
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    ABSTRACT: Maintenance of cellular homeostasis is regulated by the molecular chaperones. Under pathogenic conditions, aberrant proteins are triaged by the chaperone network. These aberrant proteins, known as "clients," have major roles in the pathogenesis of numerous neurological disorders, including tau in Alzheimer's disease, α-synuclein and LRRK2 in Parkinson's disease, SOD-1, TDP-43 and FUS in amyotrophic lateral sclerosis, and polyQ-expanded proteins such as huntingtin in Huntington's disease. Recent work has demonstrated that the use of chemical compounds which inhibit the activity of molecular chaperones subsequently alter the fate of aberrant clients. Inhibition of Hsp90 and Hsc70, two major molecular chaperones, has led to a greater understanding of how chaperone triage decisions are made and how perturbing the chaperone system can promote clearance of these pathogenic clients. Described here are major pathways and components of several prominent neurological disorders. Also discussed is how treatment with chaperone inhibitors, predominately Hsp90 inhibitors which are selective for a diseased state, can relieve the burden of aberrant client signaling in these neurological disorders.
    04/2013; 2013(Suppl 10). DOI:10.4172/2161-0460.S10-007
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