RRC ID |
53169
|
著者 |
Shioda N, Yabuki Y, Yamaguchi K, Onozato M, Li Y, Kurosawa K, Tanabe H, Okamoto N, Era T, Sugiyama H, Wada T, Fukunaga K.
|
タイトル |
Targeting G-quadruplex DNA as cognitive function therapy for ATR-X syndrome.
|
ジャーナル |
Nat Med
|
Abstract |
Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is caused by mutations in ATRX, which encodes a chromatin-remodeling protein. Genome-wide analyses in mouse and human cells indicate that ATRX tends to bind to G-rich sequences with a high potential to form G-quadruplexes. Here, we report that Atrx mutation induces aberrant upregulation of Xlr3b expression in the mouse brain, an outcome associated with neuronal pathogenesis displayed by ATR-X model mice. We show that ATRX normally binds to G-quadruplexes in CpG islands of the imprinted Xlr3b gene, regulating its expression by recruiting DNA methyltransferases. Xlr3b binds to dendritic mRNAs, and its overexpression inhibits dendritic transport of the mRNA encoding CaMKII-α, promoting synaptic dysfunction. Notably, treatment with 5-ALA, which is converted into G-quadruplex-binding metabolites, reduces RNA polymerase II recruitment and represses Xlr3b transcription in ATR-X model mice. 5-ALA treatment also rescues decreased synaptic plasticity and cognitive deficits seen in ATR-X model mice. Our findings suggest a potential therapeutic strategy to target G-quadruplexes and decrease cognitive impairment associated with ATR-X syndrome.
|
巻・号 |
24(6)
|
ページ |
802-813
|
公開日 |
2018-6-1
|
DOI |
10.1038/s41591-018-0018-6
|
PII |
10.1038/s41591-018-0018-6
|
PMID |
29785027
|
MeSH |
3' Untranslated Regions / genetics
Aminolevulinic Acid / chemistry
Aminolevulinic Acid / pharmacology
Aminolevulinic Acid / therapeutic use
Animals
Brain / metabolism
Brain-Derived Neurotrophic Factor / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Cognition*
Cytoplasmic Granules / metabolism
Cytoskeletal Proteins / metabolism
DNA / metabolism*
Dendrites / metabolism
G-Quadruplexes*
Ligands
Male
Mental Retardation, X-Linked / genetics
Mental Retardation, X-Linked / physiopathology*
Mental Retardation, X-Linked / therapy*
Mice, Inbred C57BL
Nerve Tissue Proteins / metabolism
Neuronal Plasticity
Neurons / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Binding
RNA Polymerase II / metabolism
RNA Transport
RNA, Messenger / genetics
RNA, Messenger / metabolism
Transcription, Genetic / drug effects
alpha-Thalassemia / genetics
alpha-Thalassemia / physiopathology*
alpha-Thalassemia / therapy*
|
IF |
36.13
|
引用数 |
15
|
リソース情報 |
実験動物マウス |
RBRC04937 |