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
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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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    • "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-FUS(R521G), 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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    • "Given the diversity of RNA targets directly bound by TDP-43 (64, 65), it is not inconceivable that loss of nuclear TDP-43 has detrimental effects on neuronal function. In contrast to FUS/TLS, however, solid evidence for nuclear transport deficits related to TDP-43 mutations is lacking as none of the mutations cluster around the NLS or directly affect its sequence (112). Nonetheless, inhibition of the importin α/β pathway and altered transcription profiles of genes active in import processes were associated with sporadic FTLD/ALS and increased aging (Fig. 2) (113). "
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    ABSTRACT: Aggregation of misfolded TAR DNA-binding protein 43 (TDP-43) is a striking hallmark of neurodegenerative processes that are observed in several neurological disorders, and in particular in most patients diagnosed with frontotemporal lobar degeneration (FTLD) or amyotrophic lateral sclerosis (ALS). A direct causal link with TDP-43 brain proteinopathy was provided by the identification of pathogenic mutations in TARDBP, the gene encoding TDP-43, in ALS families. However, TDP-43 proteinopathy has also been observed in carriers of mutations in several other genes associated with both ALS and FTLD demonstrating a key role for TDP-43 in neurodegeneration. To date, and despite substantial research into the biology of TDP-43, its functioning in normal brain and in neurodegeneration processes remains largely elusive. Nonetheless, breakthroughs using cellular and animal models have provided valuable insights into ALS and FTLD pathogenesis. Accumulating evidence has redirected the research focus towards a major role for impaired RNA metabolism and protein homeostasis. At the same time, the concept that toxic TDP-43 protein aggregates promote neurodegeneration is losing its credibility. This review aims at highlighting and discussing the current knowledge on TDP-43 driven pathomechanisms leading to neurodegeneration as observed in TDP-43 proteinopathies. Based on the complexity of the associated neurological diseases, a clear understanding of the essential pathological modifications will be crucial for further therapeutic interventions.
    Human Molecular Genetics 07/2013; 22(R1). DOI:10.1093/hmg/ddt349 · 6.39 Impact Factor
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