フラジャイルX症候群の治療法を見つけるには、タンパク質の損失が脳に及ぼすさまざまな影響を理解することが重要 Finding therapies for fragile X may depend on understanding the many ways protein’s loss affects brain
2022-05-17 ワシントン大学セントルイス
Researchers at Washington University School of Medicine have identified a previously unknown function for the fragile X protein, the loss of which is the leading inherited cause of intellectual disability. The researchers showed that the protein modulates how neurons in the brain’s memory center process information, a central part of learning and memory. (Image: Michael Worful/School of Medicine)
この研究成果は、5月17日発行のCell Reports誌に掲載され、脆弱性Xタンパク質の役割はこれまで考えられていたよりも複雑であり、有効な治療法を見つけるには、このタンパク質の欠損が脳に及ぼす無数の影響について、より微妙に理解する必要があることを示している。
<関連情報>
- https://source.wustl.edu/2022/05/protein-linked-to-intellectual-disability-has-complex-role/
- https://pubmed.ncbi.nlm.nih.gov/35584668/
FMRPは海馬顆粒細胞においてGABA A受容体チャネル活性を調節し、シグナル統合を制御する FMRP regulates GABA A receptor channel activity to control signal integration in hippocampal granule cells
Pan-Yue Deng, Ajeet Kumar, Valeria Cavalli, Vitaly A Klyachko
Cell Reports Published:2022 May 17
DOI: 10.1016/j.celrep.2022.110820
Abstract
Fragile X syndrome, the most common inherited form of intellectual disability, is caused by loss of fragile X mental retardation protein (FMRP). GABAergic system dysfunction is one of the hallmarks of FXS, yet the underlying mechanisms remain poorly understood. Here, we report that FMRP interacts with GABAA receptor (GABAAR) and modulates its single-channel activity. Specifically, FMRP regulates spontaneous GABAAR opening through modulating its single-channel conductance and open probability in dentate granule cells. FMRP loss reduces spontaneous GABAAR activity underlying tonic inhibition, while N-terminal FMRP fragment (aa 1-297) is sufficient to rapidly normalize tonic inhibition in Fmr1 knockout (KO) granule cells. FMRP-GABAAR interaction is supported by co-immunoprecipitation of FMRP with at least one GABAAR subunit, the α5. Functionally, FMRP-GABAAR interaction ensures accuracy of coincidence detection of granule cells, which is markedly reduced in Fmr1 KOs. Our study reveals a mechanism underlying FMRP regulation of the GABAergic system and information processing in the hippocampus.
