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
    • "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.
    Neurobiology of Disease 08/2015; 82. DOI:10.1016/j.nbd.2015.07.017 · 5.08 Impact Factor
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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.
    Nucleic Acids Research 09/2013; 42(1). DOI:10.1093/nar/gkt835 · 9.11 Impact Factor
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    • "These physical and dynamic properties of stress granules are thought to be linked to stress granule function, and thus the effects of mutant-FUS may culminate in impaired stress response and, eventually, in neurodegeneration. Although there have been no reports of overt cytotoxicity in mutant-FUS cellular models exposed to sodium arsenite or other stressors, the effects of impaired stress response may appear more distinctly as a function of age, disease progression and/or chronic stress in the human disease [19]. In fact, stress granule marker proteins have been detected within the pathological inclusions of CNS tissues from patients with ALS and FTLD [6,25], supporting the notion that stress response factors are altered during the course of disease. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Since only the mutants, but not the endogenous wild-type FUS, are associated with stress granules under most of the stress conditions reported to date, the relationship between FUS and stress granules represents a mutant-specific phenotype and thus may be of significance in mutant-induced pathogenesis. While the association of mutant-FUS with stress granules is well established, the effect of the mutant protein on stress granules has not been examined. Here we investigated the effect of mutant-FUS on stress granule formation and dynamics under conditions of oxidative stress. We found that expression of mutant-FUS delays the assembly of stress granules. However, once stress granules containing mutant-FUS are formed, they are more dynamic, larger and more abundant compared to stress granules lacking FUS. Once stress is removed, stress granules disassemble more rapidly in cells expressing mutant-FUS. These effects directly correlate with the degree of mutant-FUS cytoplasmic localization, which is induced by mutations in the nuclear localization signal of the protein. We also determine that the RGG domains within FUS play a key role in its association to stress granules. While there has been speculation that arginine methylation within these RGG domains modulates the incorporation of FUS into stress granules, our results demonstrate that this post-translational modification is not involved. Our results indicate that mutant-FUS alters the dynamic properties of stress granules, which is consistent with a gain-of-toxic mechanism for mutant-FUS in stress granule assembly and cellular stress response.
    Molecular Neurodegeneration 08/2013; 8(1):30. DOI:10.1186/1750-1326-8-30 · 6.56 Impact Factor
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