What is the key player in <scp>TDP</scp>‐43 pathology in <scp>ALS</scp>: Disappearance from the nucleus or inclusion formation in the cytoplasm?

Onodera, Osamu; Sugai, Akihiro; Konno, Tetsuo; Tada, Mari; Koyama, Akira; Nishizawa, Masatoyo

doi:10.1002/ncn3.9

Cited by 8 publications

(10 citation statements)

References 74 publications

(118 reference statements)

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“…These proteins have several characteristic features in their last exon: 1) large size; 2) a nucleotide sequence that is highly conserved among species; and 3) amino acid sequences that have been predicted to have a disordered structure ( 31 , 33 ). TDP-43 is an RNA-binding protein, and the last exon of the TARDBP gene has these characteristic features ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Increased cytoplasmicTARDBPmRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43

Koyama¹,

Sugai²,

Kato

et al. 2016

Nucleic Acids Res

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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disorder. In motor neurons of ALS, TAR DNA binding protein-43 (TDP-43), a nuclear protein encoded by TARDBP, is absent from the nucleus and forms cytoplasmic inclusions. TDP-43 auto-regulates the amount by regulating the TARDBP mRNA, which has three polyadenylation signals (PASs) and three additional alternative introns within the last exon. However, it is still unclear how the autoregulatory mechanism works and how the status of autoregulation in ALS motor neurons without nuclear TDP-43 is. Here we show that TDP-43 inhibits the selection of the most proximal PAS and induces splicing of multiple alternative introns in TARDBP mRNA to decrease the amount of cytoplasmic TARDBP mRNA by nonsense-mediated mRNA decay. When TDP-43 is depleted, the TARDBP mRNA uses the most proximal PAS and is increased in the cytoplasm. Finally, we have demonstrated that in ALS motor neurons—especially neurons with mislocalized TDP-43—the amount of TARDBP mRNA is increased in the cytoplasm. Our observations indicate that nuclear TDP-43 contributes to the autoregulation and suggests that the absence of nuclear TDP-43 induces an abnormal autoregulation and increases the amount of TARDBP mRNA. The vicious cycle might accelerate the disease progression of ALS.

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Section: Discussionmentioning

confidence: 99%

Increased cytoplasmicTARDBPmRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43

Koyama¹,

Sugai²,

Kato

et al. 2016

Nucleic Acids Res

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“…TDP-43 is the main component of ubiquitinated protein aggregates found in sporadic ALS patients, not only familial ALS [ 33 ]. In addition to this, expansion of hexanucleotide repeats in C9ORF72 increases the susceptibility for pathological alteration of TDP-34 [ 34 ]. The worldwide frequency of the C9ORF72 repeat expansion is now estimated to more than 30% for familial ALS, which represents more than 5% of the sporadic ALS cases [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic Association between Amyotrophic Lateral Sclerosis and Cancer

Taguchi

Wang

2017

Genes

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. An ALS drug, Riluzole, has been shown to induce two different anticancer effects on hepatocellular carcinoma (HCC). In light of this finding, we explore the relationship between ALS and cancer, especially for HCC, from the molecular biological viewpoint. We establish biomarkers that can discriminate between ALS patients and healthy controls. A principal component analysis (PCA) based unsupervised feature extraction (FE) is used to find gene biomarkers of ALS based on microarray gene expression data. Based on this method, 101 probes were selected as biomarkers for ALS with 95% high accuracy to discriminate between ALS patients and controls. Most of the genes corresponding to these probes are shown to be related to various cancers. These findings might provide a new insight for developing new therapeutic options or drugs for both ALS and cancer.

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“…[13][14][15] These findings raise two possibilities regarding the pathogenesis of ALS: (i) the obtaining of toxic function by cytoplasmic inclusions; or (ii) the loss of the normal nuclear function of TDP-43. 14,15 The model animals deleting TDP-43 are embryonically lethal, indicating that TDP-43 is a fundamental protein in the maintenance of cell function and survival. 16 Therefore, the loss of nuclear function in affected neurons in ALS might cause cell dysfunction or cell loss.…”

Section: Als Is a Tdp-43 Proteinopathymentioning

confidence: 98%

“…Although the molecular mechanism of the transport of TDP‐43 to cytoplasm and the formation of inclusions is unclear, researchers have speculated that the disappearance of nuclear TDP‐43 might precede the formation of visible cytoplasmic inclusions or abnormal modification, phosphorylation or ubiquitination of TDP‐43 . These findings raise two possibilities regarding the pathogenesis of ALS: (i) the obtaining of toxic function by cytoplasmic inclusions; or (ii) the loss of the normal nuclear function of TDP‐43 . The model animals deleting TDP‐43 are embryonically lethal, indicating that TDP‐43 is a fundamental protein in the maintenance of cell function and survival .…”

Section: Als Is a Tdp‐43 Proteinopathymentioning

confidence: 99%

Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases

et al. 2013

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To explore the molecular pathogenesis of amyotrophic lateral sclerosis (ALS), the nuclear function of TAR-DNA binding protein 43 kDa (TDP-43) must be elucidated. TDP-43 is a nuclear protein that colocalizes with Cajal body or Gem in cultured cells. Several recent studies have reported that the decreasing number of Gems accompanied the depletion of the causative genes for ALS, TDP-43 and FUS. Gems play an important role in the pathogenesis of spinal muscular atrophy. Gems are the sites of the maturation of spliceosomes, which are composed of uridylaterich (U) snRNAs (small nuclear RNAs) and protein complex, small nuclear ribonuclearprotein (snRNP). Spliceosomes regulate the splicing of pre-mRNA and are classified into the major or minor classes, according to the consensus sequence of acceptor and donor sites of premRNA splicing. Although the major class of spliceosomes regulates most pre-mRNA splicing, minor spliceosomes also play an important role in regulating the splicing or global speed of pre-mRNA processing. A mouse model of spinal muscular atrophy, in which the number of Gems is decreased, shows fewer subsets U snRNAs. Interestingly, in the central nervous system, U snRNAs belonging to the minor spliceosomes are markedly reduced. In ALS, the U12 snRNA is decreased only in the tissue affected by ALS and not in other tissues. Although the molecular mechanisms underlying the decreased U12 snRNA resulting in cell dysfunction and cell death in motor neuron diseases remain unclear, these findings suggest that the disturbance of nuclear bodies and minor splicing may underlie the common molecular pathogenesis of motor neuron diseases.

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What is the key player in TDP‐43 pathology in ALS: Disappearance from the nucleus or inclusion formation in the cytoplasm?

Cited by 8 publications

References 74 publications

Increased cytoplasmicTARDBPmRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43

Increased cytoplasmicTARDBPmRNA in affected spinal motor neurons in ALS caused by abnormal autoregulation of TDP-43

Genetic Association between Amyotrophic Lateral Sclerosis and Cancer

Minor splicing pathway is not minor any more: Implications for the pathogenesis of motor neuron diseases

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