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Molecular Brain
Published in: Molecular Brain 1/2013

Open Access 01-12-2013 | Research

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

Authors: 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

Published in: Molecular Brain | Issue 1/2013

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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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Metadata
Title
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
Authors
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
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2013
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/1756-6606-6-31

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