Article

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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    • "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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    • "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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