Article

Amyotrophic lateral sclerosis-associated proteins TDP-43 and FUS/TLS function in a common biochemical complex to co-regulate HDAC6 mRNA

Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 10/2010; 285(44):34097-105. DOI: 10.1074/jbc.M110.154831
Source: PubMed

ABSTRACT

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that preferentially targets motor neurons. It was recently found that dominant mutations in two related RNA-binding proteins, TDP-43 (43-kDa TAR DNA-binding domain protein) and FUS/TLS (fused in sarcoma/translated in liposarcoma) cause a subset of ALS. The convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations are suggestive of a functional relationship; however, whether or not TDP-43 and FUS/TLS operate in common biochemical pathways is not known. Here we show that TDP-43 and FUS/TLS directly interact to form a complex at endogenous expression levels in mammalian cells. Binding was mediated by an unstructured TDP-43 C-terminal domain and occurred within the context of a 300-400-kDa complex that also contained C-terminal cleavage products of TDP-43 linked to neuropathology. TDP-43 C-terminal fragments were excluded from large molecular mass TDP-43 ribonucleoprotein complexes but retained FUS/TLS binding activity. The functional significance of TDP-43-FUS/TLS complexes was established by showing that RNAi silencing of either TDP-43 or FUS/TLS reduced the expression of histone deacetylase (HDAC) 6 mRNA. TDP-43 and FUS/TLS associated with HDAC6 mRNA in intact cells and in vitro, and competition experiments suggested that the proteins occupy overlapping binding sites. The combined findings demonstrate that TDP-43 and FUS/TLS form a functional complex in intact cells and suggest that convergent ALS phenotypes associated with TDP-43 and FUS/TLS mutations may reflect their participation in common biochemical processes.

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    • "This mutation can impair binding to PPI/ CypA with respect to wild type. Johnson et al. (2009), Kim et al. (2010), Lauranzano et al. (2015), McDonald et al. (2011) p.R361T Chiang et al.(2012) n.d. p.P363A Daoud et al. (2009) n.d. "
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    ABSTRACT: At present, there are very few therapeutic options for patients affected by amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, almost all patients affected by ALS or tau-negative FTD share in their brains the presence of aggregated TDP-43, a nuclear factor that plays an important role in regulating RNA metabolism. For this reason, this protein represents a very promising target to develop novel therapeutic options. Over the years, these options have mostly involved the search for new effectors capable of reducing aberrant aggregation or enhancing its clearance by UPS-dependent protein quality control or autophagy system. Targeting eventual mutations in the sequence of this protein might represent a parallel alternative therapeutic option. To this date, the study of various patient populations has allowed to find more than 50 mutations associated with disease. It is, therefore, important to better understand what the functional consequences of these mutations are. As discussed in this review, the emerging picture is that most TDP-43 mutations appear to directly relate to specific disease features such as increased aggregation, half-life, or altered cellular localization and protein-protein interactions.
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    • "FUShasbeenreportedtoco-localizewithTDP-43innuclear complexes(Kimetal.,2010b;Lingetal.,2010)andinlarger cytoplasmiccomplexes(Kimetal.,2010b).PurifiedFUShas alsobeenreportedtointeractwithpurifiedHis-taggedTDP- 43invitroinanRNA-independentmanner,associatedtothe C-terminalregionofTDP-43(Kimetal.,2010b).Theseubiq- uitouslyexpressedbindingproteinsseemtohavesimilarand complementaryfunctions. OnlythemutantformofFUSwasfoundinstressgranules inreponsetotranslationalarrest(Boscoetal.,2010).FUSand TDP-43wereobservedtoco-localizeincytoplasmicaggregations ofALS/FTLD-affectedneurons(DaCruzandCleveland,2011). "
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    ABSTRACT: Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by degeneration of the fronto temporal lobes and abnormal protein inclusions. It exhibits a broad clinicopathological spectrum and has been linked to mutations in seven different genes. We will provide a picture, which connects the products of these genes, albeit diverse in nature and function, in a network. Despite the paucity of information available for some of these genes, we believe that RNA processing and post-transcriptional regulation of gene expression might constitute a common theme in the network. Recent studies have unraveled the role of mutations affecting the functions of RNA binding proteins and regulation of microRNAs. This review will combine all the recent findings on genes involved in the pathogenesis of FTD, highlighting the importance of a common network of interactions in order to study and decipher the heterogeneous clinical manifestations associated with FTD. This approach could be helpful for the research of potential therapeutic strategies.
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    • "HDAC6 is essential for autophagosome-lysosome fusion and protein aggregate clearance (Lee et al., 2010). TARDBP directly binds HDAC6 mRNA within the coding region and is necessary to maintain its physiological level (Fiesel et al., 2010;Kim et al., 2010). HDAC6 downregulation after TARDBP silencing was associated with impaired cellular turnover of aggregating proteins and reduced neurite outgrowth (Fiesel et al., 2010Fiesel et al., , 2011). "

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