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Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function...

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Autores principales: Shiga, Atsushi, Ishihara, Tomohiko, Miyashita, Akinori, Kuwabara, Misaki, Kato, Taisuke, Watanabe, Norihiro, Yamahira, Akie, Kondo, Chigusa, Yokoseki, Akio, Takahashi, Masuhiro, Kuwano, Ryozo, Kakita, Akiyoshi, Nishizawa, Masatoyo, Takahashi, Hitoshi, Onodera, Osamu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416794/
https://www.ncbi.nlm.nih.gov/pubmed/22900096
http://dx.doi.org/10.1371/journal.pone.0043120
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author Shiga, Atsushi
Ishihara, Tomohiko
Miyashita, Akinori
Kuwabara, Misaki
Kato, Taisuke
Watanabe, Norihiro
Yamahira, Akie
Kondo, Chigusa
Yokoseki, Akio
Takahashi, Masuhiro
Kuwano, Ryozo
Kakita, Akiyoshi
Nishizawa, Masatoyo
Takahashi, Hitoshi
Onodera, Osamu
author_facet Shiga, Atsushi
Ishihara, Tomohiko
Miyashita, Akinori
Kuwabara, Misaki
Kato, Taisuke
Watanabe, Norihiro
Yamahira, Akie
Kondo, Chigusa
Yokoseki, Akio
Takahashi, Masuhiro
Kuwano, Ryozo
Kakita, Akiyoshi
Nishizawa, Masatoyo
Takahashi, Hitoshi
Onodera, Osamu
author_sort Shiga, Atsushi
collection PubMed
description Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS.
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spelling pubmed-34167942012-08-16 Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS Shiga, Atsushi Ishihara, Tomohiko Miyashita, Akinori Kuwabara, Misaki Kato, Taisuke Watanabe, Norihiro Yamahira, Akie Kondo, Chigusa Yokoseki, Akio Takahashi, Masuhiro Kuwano, Ryozo Kakita, Akiyoshi Nishizawa, Masatoyo Takahashi, Hitoshi Onodera, Osamu PLoS One Research Article Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease caused by selective loss of motor neurons. In the ALS motor neurons, TAR DNA-binding protein of 43 kDa (TDP-43) is dislocated from the nucleus to cytoplasm and forms inclusions, suggesting that loss of a nuclear function of TDP-43 may underlie the pathogenesis of ALS. TDP-43 functions in RNA metabolism include regulation of transcription, mRNA stability, and alternative splicing of pre-mRNA. However, a function of TDP-43 in tissue affected with ALS has not been elucidated. We sought to identify the molecular indicators reflecting on a TDP-43 function. Using exon array analysis, we observed a remarkable alteration of splicing in the polymerase delta interacting protein 3 (POLDIP3) as a result of the depletion of TDP-43 expression in two types of cultured cells. In the cells treated with TDP-43 siRNA, wild-type POLDIP3 (variant-1) decreased and POLDIP3 lacking exon 3 (variant-2) increased. The RNA binding ability of TDP-43 was necessary for inclusion of POLDIP3 exon 3. Moreover, we found an increment of POLDIP3 variant-2 mRNA in motor cortex, spinal cord and spinal motor neurons collected by laser capture microdissection with ALS. Our results suggest a loss of TDP-43 function in tissues affected with ALS, supporting the hypothesis that a loss of function of TDP-43 underlies the pathogenesis of ALS. Public Library of Science 2012-08-10 /pmc/articles/PMC3416794/ /pubmed/22900096 http://dx.doi.org/10.1371/journal.pone.0043120 Text en © 2012 Shiga et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Shiga, Atsushi
Ishihara, Tomohiko
Miyashita, Akinori
Kuwabara, Misaki
Kato, Taisuke
Watanabe, Norihiro
Yamahira, Akie
Kondo, Chigusa
Yokoseki, Akio
Takahashi, Masuhiro
Kuwano, Ryozo
Kakita, Akiyoshi
Nishizawa, Masatoyo
Takahashi, Hitoshi
Onodera, Osamu
Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS
title Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS
title_full Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS
title_fullStr Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS
title_full_unstemmed Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS
title_short Alteration of POLDIP3 Splicing Associated with Loss of Function of TDP-43 in Tissues Affected with ALS
title_sort alteration of poldip3 splicing associated with loss of function of tdp-43 in tissues affected with als
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3416794/
https://www.ncbi.nlm.nih.gov/pubmed/22900096
http://dx.doi.org/10.1371/journal.pone.0043120
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