DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5
Abstract Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine‐mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathome...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2019-04-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201708547 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850204062780227584 |
|---|---|
| author | Naohide Kondo Genki Tohnai Kentaro Sahashi Madoka Iida Mayumi Kataoka Hideaki Nakatsuji Yutaka Tsutsumi Atsushi Hashizume Hiroaki Adachi Haruki Koike Keiko Shinjo Yutaka Kondo Gen Sobue Masahisa Katsuno |
| author_facet | Naohide Kondo Genki Tohnai Kentaro Sahashi Madoka Iida Mayumi Kataoka Hideaki Nakatsuji Yutaka Tsutsumi Atsushi Hashizume Hiroaki Adachi Haruki Koike Keiko Shinjo Yutaka Kondo Gen Sobue Masahisa Katsuno |
| author_sort | Naohide Kondo |
| collection | DOAJ |
| description | Abstract Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine‐mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG‐rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper‐methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over‐expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper‐methylation underlies the neurodegeneration in SBMA. |
| format | Article |
| id | doaj-art-3b53acade81c4e8ebab35318515fcdcb |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2019-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-3b53acade81c4e8ebab35318515fcdcb2025-08-20T02:11:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842019-04-0111511910.15252/emmm.201708547DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5Naohide Kondo0Genki Tohnai1Kentaro Sahashi2Madoka Iida3Mayumi Kataoka4Hideaki Nakatsuji5Yutaka Tsutsumi6Atsushi Hashizume7Hiroaki Adachi8Haruki Koike9Keiko Shinjo10Yutaka Kondo11Gen Sobue12Masahisa Katsuno13Department of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDepartment of Neurology, University of Occupational and Environmental Health School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineDivision of Cancer Biology, Nagoya University Graduate School of MedicineDivision of Cancer Biology, Nagoya University Graduate School of MedicineResearch Division of Dementia and Neurodegenerative Disease, Nagoya University Graduate School of MedicineDepartment of Neurology, Nagoya University Graduate School of MedicineAbstract Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine‐mediated neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. While transcriptional dysregulation is known to play a critical role in the pathogenesis of SBMA, the underlying molecular pathomechanisms remain unclear. DNA methylation is a fundamental epigenetic modification that silences the transcription of various genes that have a CpG‐rich promoter. Here, we showed that DNA methyltransferase 1 (Dnmt1) is highly expressed in the spinal motor neurons of an SBMA mouse model and in patients with SBMA. Both genetic Dnmt1 depletion and treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells. Furthermore, a continuous intracerebroventricular injection of RG108 mitigated the phenotype of SBMA mice. DNA methylation array analysis identified hairy and enhancer of split 5 (Hes5) as having a CpG island with hyper‐methylation in the promoter region, and the Hes5 expression was strongly silenced in SBMA. Moreover, Hes5 over‐expression rescued the SBMA cells possibly by inducing Smad2 phosphorylation. Our findings suggest DNA hyper‐methylation underlies the neurodegeneration in SBMA.https://doi.org/10.15252/emmm.201708547DNA methylationepigeneticsHes5RG108spinal and bulbar muscular atrophy |
| spellingShingle | Naohide Kondo Genki Tohnai Kentaro Sahashi Madoka Iida Mayumi Kataoka Hideaki Nakatsuji Yutaka Tsutsumi Atsushi Hashizume Hiroaki Adachi Haruki Koike Keiko Shinjo Yutaka Kondo Gen Sobue Masahisa Katsuno DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 EMBO Molecular Medicine DNA methylation epigenetics Hes5 RG108 spinal and bulbar muscular atrophy |
| title | DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 |
| title_full | DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 |
| title_fullStr | DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 |
| title_full_unstemmed | DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 |
| title_short | DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 |
| title_sort | dna methylation inhibitor attenuates polyglutamine induced neurodegeneration by regulating hes5 |
| topic | DNA methylation epigenetics Hes5 RG108 spinal and bulbar muscular atrophy |
| url | https://doi.org/10.15252/emmm.201708547 |
| work_keys_str_mv | AT naohidekondo dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT genkitohnai dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT kentarosahashi dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT madokaiida dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT mayumikataoka dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT hideakinakatsuji dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT yutakatsutsumi dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT atsushihashizume dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT hiroakiadachi dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT harukikoike dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT keikoshinjo dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT yutakakondo dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT gensobue dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 AT masahisakatsuno dnamethylationinhibitorattenuatespolyglutamineinducedneurodegenerationbyregulatinghes5 |