TDP-43 and FUS: a nuclear affair

Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University and German Center for Neurodegenerative Diseases (DZNE) Munich, Schillerstr. 44, 80336 Munich, Germany.
Trends in Neurosciences (Impact Factor: 13.56). 06/2011; 34(7). DOI: 10.1016/j.tins.2011.05.002
Source: PubMed


Misfolded TAR DNA binding protein 43 (TDP-43) and Fused-In-Sarcoma (FUS) protein have recently been identified as pathological hallmarks of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) characterized by the presence of ubiquitin-positive inclusions (FTLD-U). Although TDP-43 and FUS are normally located predominantly in the nucleus, pathological TDP-43 and FUS inclusions are mostly found in the cytosol. Cytosolic deposition is paralleled by a striking nuclear depletion of either protein. Based on a number of recent findings, we postulate that defects in nuclear import are an important step towards TDP-43 and FUS dysfunction. Failure of nuclear transport can arise from mutations within a nuclear localization signal or from age-related decline of nuclear import mechanisms. We propose that nuclear import defects in combination with additional hits, for example cellular stress and genetic risk factors, may be a central underlying cause of ALS and FTLD-U pathology.

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Available from: Dorothee Dormann, Sep 08, 2014
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    • "TDP-43 and FUS are highly conserved DNA and RNA-binding proteins with roles in transcriptional repression, pre-mRNA splicing and localized translation (Bentmann et al., 2013); and like hGle1, TDP-43 also facilitates stress granule assembly (McDonald et al., 2011). Many of the mutations catalogued for such genes encode proteins with low complexity glycine-rich, prion-like domains that promote their cytoplasmic aggregation and loss of nuclear functions (Dormann and Haass, 2011). "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a lethal late onset motor neuron disease with underlying cellular defects in RNA metabolism. In prior studies, two deleterious heterozygous mutations in the gene encoding human (h)Gle1 were identified in ALS patients. hGle1 is an mRNA processing modulator that requires inositol hexakisphosphate (IP6) binding for function. Interestingly, one hGLE1 mutation (c.1965-2A>C) results in a novel 88 amino acid C-terminal insertion, generating an altered protein. Like hGle1A, at steady state, the altered protein termed hGle1-IVS14-2A>C is absent from the nuclear envelope rim and localizes to the cytoplasm. hGle1A performs essential cytoplasmic functions in translation and stress granule regulation. Therefore, we speculated that the ALS disease pathology results from altered cellular pools of hGle1 and increased cytoplasmic hGle1 activity. GFP-hGle1-IVS14-2A>C localized to stress granules comparably to GFP-hGle1A, and rescued stress granule defects following siRNA-mediated hGle1 depletion. As described for hGle1A, overexpression of the hGle1-IVS14-2A>C protein also induced formation of larger SGs. Interestingly, hGle1A and the disease associated hGle1-IVS14-2A>C overexpression induced the formation of distinct cytoplasmic protein aggregates that appear similar to those found in neurodegenerative diseases. Strikingly, the ALS-linked hGle1-IVS14-2A>C protein also rescued mRNA export defects upon depletion of endogenous hGle1, acting in a potentially novel bi-functional manner. We conclude that the ALS-linked hGle1-c.1965-2A>C mutation generates a protein isoform capable of both hGle1A- and hGle1B-ascribed functions, and thereby uncoupled from normal mechanisms of hGle1 regulation.
    Full-text · Article · Nov 2015 · Advances in Biological Regulation
    • "The methylated form of FUS (meFUS) is assumed to be localized within the nucleus predominantly (Dormann et al., 2012). FUS mutations within the C-terminal part typically lead to a selective nuclear import defect which results in a cytoplasmic mislocalization of FUS due to the disruption of the nuclear localization signal (NLS) (Bosco et al., 2010; Dormann et al., 2010; Gal et al., 2011; Vance et al., 2009, 2013; Zhang and Chook, 2012). Import defects of FUS are being suggested as key events in ALS pathogenesis (Dormann et al., 2010, 2012; Niu et al., 2012). "
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    ABSTRACT: Autosomal-dominant mutations within the gene FUS (Fused in Sarcoma) are responsible for 5% of familial cases of Amyotrophic Lateral Sclerosis (ALS). The FUS protein is physiologically mainly located in the nucleus, while cytoplasmic FUS aggregates are pathological hallmarks of FUS-ALS. Data from non-neuronal cell models and/or models using heterologous expression of FUS mutants suggest cytoplasmic FUS translocation as a pivotal initial event which leads to neurodegeneration depending on a second hit. Here we present the first human model of FUS-ALS using patient-derived neurons carrying endogenous FUS mutations leading to a benign (R521C) or a more severe clinical phenotype (frameshift mutation R495QfsX527). We thereby showed that the severity of the underlying FUS mutation determines the amount of cytoplasmic FUS accumulation and cellular vulnerability to exogenous stress. Cytoplasmic FUS inclusions formed spontaneously depending on both, severity of FUS mutation and neuronal aging. These aggregates showed typical characteristics of FUS-ALS including methylated FUS. Finally, neurodegeneration was not specific to layer V cortical neurons perfectly in line with the current model of disease spreading in ALS. Our study highlights the value and usefulness of patient-derived cell models in FUS-ALS. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Aug 2015 · Neurobiology of Disease
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    • "The mechanism/s by which dominant mutations in FUS might result in ALS are unclear, however. It has been suggested that FUS mutations, many of which result in sequestration of the mutant protein in the cytoplasm, can form toxic protein aggregates, or that the mutations act in a dominant loss-of-function manner (e.g. by sequestering other proteins into inactive RNA processing complexes) (8,25,30). In both of these scenarios, it is plausible that the outcome relevant to ALS is loss of critical mRNA species. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is associated with progressive degeneration of motor neurons. Several of the genes associated with this disease encode proteins involved in RNA processing, including fused-in-sarcoma/translocated-in-sarcoma (FUS/TLS). FUS is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family of proteins that bind thousands of pre-mRNAs and can regulate their splicing. Here, we have examined the possibility that FUS is also a component of the cellular response to DNA damage. We show that both GFP-tagged and endogenous FUS re-localize to sites of oxidative DNA damage induced by UVA laser, and that FUS recruitment is greatly reduced or ablated by an inhibitor of poly (ADP-ribose) polymerase activity. Consistent with this, we show that recombinant FUS binds directly to poly (ADP-ribose) in vitro, and that both GFP-tagged and endogenous FUS fail to accumulate at sites of UVA laser induced damage in cells lacking poly (ADP-ribose) polymerase-1. Finally, we show that GFP-FUSR521G, harbouring a mutation that is associated with ALS, exhibits reduced ability to accumulate at sites of UVA laser-induced DNA damage. Together, these data suggest that FUS is a component of the cellular response to DNA damage, and that defects in this response may contribute to ALS.
    Full-text · Article · Sep 2013 · Nucleic Acids Research
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