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はじめに
近年,microRNA(以下,miRNA)と呼ばれる小分子RNAの研究が驚異的な発展をしている。miRNAは,21塩基前後の長さのnon-coding RNAの1種で,遺伝子発現を転写後レベルで抑制する機能性RNAである。多くのmiRNAの発現は,時間的・空間的に制御されており,ある発生時期だけ,あるいは特定の臓器・細胞だけに発現しており,細胞の発生分化・機能維持に必須であることが明らかとなってきた。また同時に,miRNAの発現や機能の異常は,さまざまな疾患の病態メカニズムとも深く関わっており,診断や治療のターゲットとして臨床的にも注目度が高まってきている。神経科学の分野においても,この5年ほどの間に,神経細胞の発生・維持に必須のmiRNAが次々と同定され,シナプスの形成にも重要な役割を担っていることがわかってきた。またパーキンソン病やアルツハイマー病など神経変性疾患と関連している可能性のあるmiRNAも報告されつつある。
本稿では,まずmiRNAの生成・機能メカニズムについて概説し,その後,脳に高発現する代表的なmiRNAの持つ機能と,さらに神経・精神疾患との関わりについての最近の知見を紹介する。
Abstract
MicroRNAs have emerged as a new regulatory factor of gene expression. They mediate translational repression or degradation of their target mRNAs by RNA interference (RNAi). The expression of each microRNA is tightly regulated in a development- and cell-specific manner by various mechanisms such as blockade of let-7 family expression by Lin-28 or RNA editing. They also act as regulatory switches for development, organogenesis, and cellular differentiation or for controlling distinct functions that are required for the maintenance of each tissue and cell subtypes.
The abundant expression of microRNAs as well as the exclusive expression of certain microRNAs in the central nervous system highlights their biological importance at all stages of neural development and in postmitotic and differentiated neurons. Further, some microRNAs, such as miRNA-134, and miRNA-132 are localized and are synthesized in part at synaptic sites in dendrites to regulate synaptic formation and plasticity.
In addition to the imparting of basic knowledge about the biogenesis and mechanism of action of microRNAs,this review focuses on the recent advances in microRNA studies in neurobiology,including the expression pattern of microRNAs in the mammalian brain,the role of microRNAs in neural differentiation and maturation,formation and plasticity of synaptic connections,and maintenance of neural function such as the synthesis of the neurotransmitters in selected neurons. Finally,the possible connection between microRNA dysfunction and neurological diseases,and future implications for diagnosis,and treatment of defects in human brain development and neurodegenerative diseases are discussed.
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