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 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.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5 ; volume:11 ; number:5 ; year:2019 ; extent:19
EMBO molecular medicine / European Molecular Biology Organization ; 11, Heft 5 (2019) (gesamt 19)
- Urheber
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Kondo, Naohide
Tohnai, Genki
Sahashi, Kentaro
Iida, Madoka
Kataoka, Mayumi
Nakatsuji, Hideaki
Tsutsumi, Yutaka
Hashizume, Atsushi
Adachi, Hiroaki
Koike, Haruki
Shinjo, Keiko
Kondo, Yutaka
Sobue, Gen
Katsuno, Masahisa
- DOI
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10.15252/emmm.201708547
- URN
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urn:nbn:de:101:1-2022080808041160921557
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:23 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Kondo, Naohide
- Tohnai, Genki
- Sahashi, Kentaro
- Iida, Madoka
- Kataoka, Mayumi
- Nakatsuji, Hideaki
- Tsutsumi, Yutaka
- Hashizume, Atsushi
- Adachi, Hiroaki
- Koike, Haruki
- Shinjo, Keiko
- Kondo, Yutaka
- Sobue, Gen
- Katsuno, Masahisa
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