Mackenzie, I. R., Rademakers, R. & Neumann, M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 9, 995-1007

Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada.
The Lancet Neurology (Impact Factor: 21.9). 10/2010; 9(10):995-1007. DOI: 10.1016/S1474-4422(10)70195-2
Source: PubMed


Abnormal intracellular protein aggregates comprise a key characteristic in most neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The seminal discoveries of accumulation of TDP-43 in most cases of ALS and the most frequent form of FTD, frontotemporal lobar degeneration with ubiquitinated inclusions, followed by identification of FUS as the novel pathological protein in a small subset of patients with ALS and various FTD subtypes provide clear evidence that these disorders are related. The creation of a novel molecular classification of ALS and FTD based on the identity of the predominant protein abnormality has, therefore, been possible. The striking functional and structural similarities of TDP-43 and FUS, which are both DNA/RNA binding proteins, imply that abnormal RNA metabolism is a pivotal event, but the mechanisms leading to TDP-43 and FUS accumulation and the resulting neurodegeneration are currently unknown. Nonetheless, TDP-43 and FUS are promising candidates for the development of novel biomarker assays and targeted therapies.

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    • "Fused in sarcoma/translocated in liposarcoma (FUS/TLS) is a member of the FET (TET) family, which includes EWS/EWSR1 (Ewing sarcoma breakpoint region 1) and TAF15/TAFII68 (TATA-binding protein-associated factor II, 68 kDa). The characteristic of this family of proteins is that they are ubiquitously expressed RNA-binding proteins that are components of fusion oncogenes that cause human cancers (Tan and Manley 2009; Mackenzie et al. 2010). Recent studies have revealed that mutations in these genes are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) (Kwiatkowski et al. 2009; Vance et al. 2009; Ticozzi et al. 2011; Couthouis et al. 2012). "
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    ABSTRACT: More than half of all human genes produce prematurely terminated polyadenylated short mRNAs. However, the underlying mechanisms remain largely elusive. CLIP-seq (cross-linking immunoprecipitation [CLIP] combined with deep sequencing) of FUS (fused in sarcoma) in neuronal cells showed that FUS is frequently clustered around an alternative polyadenylation (APA) site of nascent RNA. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing) of RNA polymerase II (RNAP II) demonstrated that FUS stalls RNAP II and prematurely terminates transcription. When an APA site is located upstream of an FUS cluster, FUS enhances polyadenylation by recruiting CPSF160 and up-regulates the alternative short transcript. In contrast, when an APA site is located downstream from an FUS cluster, polyadenylation is not activated, and the RNAP II-suppressing effect of FUS leads to down-regulation of the alternative short transcript. CAGE-seq (cap analysis of gene expression [CAGE] combined with deep sequencing) and PolyA-seq (a strand-specific and quantitative method for high-throughput sequencing of 3' ends of polyadenylated transcripts) revealed that position-specific regulation of mRNA lengths by FUS is operational in two-thirds of transcripts in neuronal cells, with enrichment in genes involved in synaptic activities. © 2015 Masuda et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & development 05/2015; 29(10):1045-57. DOI:10.1101/gad.255737.114 · 10.80 Impact Factor
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    • "Some proteins are accumulated in a broad range of neurodegenerative diseases. For example, abnormal accumulation of TDP-43 and FUS/TUS is also observed in AD, HD, and other polyglutamine diseases [2] [3] [4] [5]. "
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    ABSTRACT: Impaired DNA damage repair is a common pathological endophenotype of some types of neurodegenerative diseases, intellectual disabilities, and psychiatric diseases. Dysfunctional DNA repair and DNA damage, including DNA double-stranded breaks, are linked to transcriptional dysfunction and abnormal DNA methylation. Impaired DNA repair in neural stem cells leads to microcephaly or cerebellar ataxia. Furthermore, DNA repair defects and DNA damage in mature neurons lead to progressive cognitive impairment, which might be a common feature of Alzheimer's disease, Huntington's disease, and other polyglutamine diseases. Oxidative DNA damage and altered DNA repair gene expression are observed in GABAergic neurons in schizophrenia. These findings indicate that impaired DNA repair is a common pathological endophenotype of neurological diseases, and that DNA damage might lead to diverse disease symptoms dependent on timing and the affected cell type.
    Current Molecular Medicine 03/2015; 15(2). DOI:10.2174/1566524015666150303002556 · 3.62 Impact Factor
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    • "Nevertheless, FUS predominantly localizes to the nucleus of healthy cells, whereas in ALS patients with FUS mutations, pathological protein is redistributed to the cytoplasm of affected cells where it accumulates and aggregates (Fig. 2B). This mislocalization leads to partial loss of nuclear protein (Mackenzie et al., 2010; Vance et al., 2009), similarly to TDP-43 pathology. The majority of FUS mutations are clustered in the NLS sequence, which is embedded within the highly conserved extreme C-terminus (Lagier-Tourenne et al., 2010; Ling et al., 2013). "
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    ABSTRACT: Propagation of pathological protein assemblies via a prion-like mechanism has been suggested to drive neurodegenerative diseases, such as Parkinson's and Alzheimer's. Recently, amyotrophic lateral sclerosis (ALS)-linked proteins, such as SOD1, TDP-43 and FUS were shown to follow self-perpetuating seeded aggregation, thereby adding ALS to the group of prion-like disorders. The cell-to-cell spread of these pathological protein assemblies and their pathogenic mechanism is poorly understood. However, as ALS is a non-cell autonomous disease and pathology in glial cells was shown to contribute to motor neuron damage, spreading mechanisms are likely to underlie disease progression via the interplay between affected neurons and their neighboring glial cells.
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