The long non-coding RNA nuclear-enriched abundant transcript 1-2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis

Yoshinori Nishimoto, Shinichi Nakagawa, Tetsuro Hirose, Hirotaka James Okano, Masaki Takao, Shinsuke Shibata, Satoshi Suyama, Ken Ichiro Kuwako, Takao Imai, Shigeo Murayama, Norihiro Suzuki, Hideyuki Okano

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Abstract

Background: A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1-2 (NEAT1-2), constitutes nuclear bodies known as "paraspeckles". Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons. Results: In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1-2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1-2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1-2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1-2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1-2 lncRNA. The observation indicating specific assembly of NEAT1-2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation. Conclusions: NEAT1-2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.

Original languageEnglish
Article number31
JournalMolecular Brain
Volume6
Issue number1
DOIs
Publication statusPublished - 2013

Fingerprint

Long Noncoding RNA
Amyotrophic Lateral Sclerosis
Motor Neurons
RNA-Binding Proteins
Liposarcoma
DNA-Binding Proteins
Sarcoma
In Situ Hybridization
RNA
Motor Neuron Disease
Consciousness
Immunoprecipitation
Neurodegenerative Diseases

Keywords

  • Amyotrophic lateral sclerosis
  • Electron microscopy
  • FUS/TLS
  • Long non-coding RNA
  • NEAT1-2
  • Paraspeckle
  • TDP-43

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Molecular Biology
  • Medicine(all)

Cite this

The long non-coding RNA nuclear-enriched abundant transcript 1-2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis. / Nishimoto, Yoshinori; Nakagawa, Shinichi; Hirose, Tetsuro; Okano, Hirotaka James; Takao, Masaki; Shibata, Shinsuke; Suyama, Satoshi; Kuwako, Ken Ichiro; Imai, Takao; Murayama, Shigeo; Suzuki, Norihiro; Okano, Hideyuki.

In: Molecular Brain, Vol. 6, No. 1, 31, 2013.

Research output: Contribution to journalArticle

Nishimoto, Yoshinori ; Nakagawa, Shinichi ; Hirose, Tetsuro ; Okano, Hirotaka James ; Takao, Masaki ; Shibata, Shinsuke ; Suyama, Satoshi ; Kuwako, Ken Ichiro ; Imai, Takao ; Murayama, Shigeo ; Suzuki, Norihiro ; Okano, Hideyuki. / The long non-coding RNA nuclear-enriched abundant transcript 1-2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis. In: Molecular Brain. 2013 ; Vol. 6, No. 1.
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abstract = "Background: A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1-2 (NEAT1-2), constitutes nuclear bodies known as {"}paraspeckles{"}. Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons. Results: In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1-2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1-2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1-2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1-2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1-2 lncRNA. The observation indicating specific assembly of NEAT1-2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation. Conclusions: NEAT1-2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.",
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author = "Yoshinori Nishimoto and Shinichi Nakagawa and Tetsuro Hirose and Okano, {Hirotaka James} and Masaki Takao and Shinsuke Shibata and Satoshi Suyama and Kuwako, {Ken Ichiro} and Takao Imai and Shigeo Murayama and Norihiro Suzuki and Hideyuki Okano",
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T1 - The long non-coding RNA nuclear-enriched abundant transcript 1-2 induces paraspeckle formation in the motor neuron during the early phase of amyotrophic lateral sclerosis

AU - Nishimoto, Yoshinori

AU - Nakagawa, Shinichi

AU - Hirose, Tetsuro

AU - Okano, Hirotaka James

AU - Takao, Masaki

AU - Shibata, Shinsuke

AU - Suyama, Satoshi

AU - Kuwako, Ken Ichiro

AU - Imai, Takao

AU - Murayama, Shigeo

AU - Suzuki, Norihiro

AU - Okano, Hideyuki

PY - 2013

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N2 - Background: A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1-2 (NEAT1-2), constitutes nuclear bodies known as "paraspeckles". Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons. Results: In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1-2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1-2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1-2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1-2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1-2 lncRNA. The observation indicating specific assembly of NEAT1-2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation. Conclusions: NEAT1-2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.

AB - Background: A long non-coding RNA (lncRNA), nuclear-enriched abundant transcript 1-2 (NEAT1-2), constitutes nuclear bodies known as "paraspeckles". Mutations of RNA binding proteins, including TAR DNA-binding protein-43 (TDP-43) and fused in sarcoma/translocated in liposarcoma (FUS/TLS), have been described in amyotrophic lateral sclerosis (ALS). ALS is a devastating motor neuron disease, which progresses rapidly to a total loss of upper and lower motor neurons, with consciousness sustained. The aim of this study was to clarify the interaction of paraspeckles with ALS-associated RNA-binding proteins, and to identify increased occurrence of paraspeckles in the nucleus of ALS spinal motor neurons. Results: In situ hybridization (ISH) and ultraviolet cross-linking and immunoprecipitation were carried out to investigate interactions of NEAT1-2 lncRNA with ALS-associated RNA-binding proteins, and to test if paraspeckles form in ALS spinal motor neurons. As the results, TDP-43 and FUS/TLS were enriched in paraspeckles and bound to NEAT1-2 lncRNA directly. The paraspeckles were localized apart from the Cajal bodies, which were also known to be related to RNA metabolism. Analyses of 633 human spinal motor neurons in six ALS cases showed NEAT1-2 lncRNA was upregulated during the early stage of ALS pathogenesis. In addition, localization of NEAT1-2 lncRNA was identified in detail by electron microscopic analysis combined with ISH for NEAT1-2 lncRNA. The observation indicating specific assembly of NEAT1-2 lncRNA around the interchromatin granule-associated zone in the nucleus of ALS spinal motor neurons verified characteristic paraspeckle formation. Conclusions: NEAT1-2 lncRNA may act as a scaffold of RNAs and RNA binding proteins in the nuclei of ALS motor neurons, thereby modulating the functions of ALS-associated RNA-binding proteins during the early phase of ALS. These findings provide the first evidence of a direct association between paraspeckle formation and a neurodegenerative disease, and may shed light on the development of novel therapeutic targets for the treatment of ALS.

KW - Amyotrophic lateral sclerosis

KW - Electron microscopy

KW - FUS/TLS

KW - Long non-coding RNA

KW - NEAT1-2

KW - Paraspeckle

KW - TDP-43

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