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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3416794?pdf=render |
| _version_ | 1818132549724012544 |
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| author | Atsushi Shiga Tomohiko Ishihara Akinori Miyashita Misaki Kuwabara Taisuke Kato Norihiro Watanabe Akie Yamahira Chigusa Kondo Akio Yokoseki Masuhiro Takahashi Ryozo Kuwano Akiyoshi Kakita Masatoyo Nishizawa Hitoshi Takahashi Osamu Onodera |
| author_facet | Atsushi Shiga Tomohiko Ishihara Akinori Miyashita Misaki Kuwabara Taisuke Kato Norihiro Watanabe Akie Yamahira Chigusa Kondo Akio Yokoseki Masuhiro Takahashi Ryozo Kuwano Akiyoshi Kakita Masatoyo Nishizawa Hitoshi Takahashi Osamu Onodera |
| author_sort | Atsushi Shiga |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-11T08:38:36Z |
| format | Article |
| id | doaj.art-fd6d5c3d72e94dc3a0cac8c1ae4623f7 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-11T08:38:36Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-fd6d5c3d72e94dc3a0cac8c1ae4623f72022-12-22T01:14:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0178e4312010.1371/journal.pone.0043120Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS.Atsushi ShigaTomohiko IshiharaAkinori MiyashitaMisaki KuwabaraTaisuke KatoNorihiro WatanabeAkie YamahiraChigusa KondoAkio YokosekiMasuhiro TakahashiRyozo KuwanoAkiyoshi KakitaMasatoyo NishizawaHitoshi TakahashiOsamu OnoderaAmyotrophic 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.http://europepmc.org/articles/PMC3416794?pdf=render |
| spellingShingle | Atsushi Shiga Tomohiko Ishihara Akinori Miyashita Misaki Kuwabara Taisuke Kato Norihiro Watanabe Akie Yamahira Chigusa Kondo Akio Yokoseki Masuhiro Takahashi Ryozo Kuwano Akiyoshi Kakita Masatoyo Nishizawa Hitoshi Takahashi Osamu Onodera Alteration of POLDIP3 splicing associated with loss of function of TDP-43 in tissues affected with ALS. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC3416794?pdf=render |
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