Thomas Laura, Pasquini María Verónica Galante, Pasquini Laura Andrea
National Scientific and Technical Research Council. Prof. Dr. Alejandro C. Paladini Institute of Biological Chemistry and Physicochemistry, School of Pharmacy and Biochemistry, Universidad de Buenos Aires, Junín 956, C1113, Buenos Aires, Argentina.
School of Exact and Natural Sciences, Universidad de Buenos Aires, Buenos Aires, Argentina.
Mol Neurobiol. 2025 Jun 24. doi: 10.1007/s12035-025-05144-5.
Synthesized by oligodendrocytes (OLGs) in the central nervous system (CNS), the myelin sheath is a multilamellar structure that enables the rapid transmission of action potentials and provides metabolic support to the axons it surrounds. In multiple sclerosis (MS), a chronic neurological disorder, the myelin membrane becomes the target of immune-mediated attacks. These attacks trigger the release of inflammatory cytokines and activate microglia (MG) and astrocytes, leading to severe demyelination and neurodegeneration. Quaking (QKI) is a multifunctional RNA-binding protein that plays a critical role in CNS myelination by regulating RNA metabolism and lipid homeostasis in glial cells. Through its major isoforms-QKI-5, QKI-6, and QKI-7-QKI orchestrates essential post-transcriptional processes in OLGs, including splicing, stability, nuclear export, and local translation of key myelin transcripts. QKI deficiency alters the expression of numerous genes involved in axonal ensheathment and myelination pathways, such as MBP, PLP1, MAG, and Nfasc155. QKI also modulates cholesterol and fatty acid biosynthesis by acting as a transcriptional coactivator, ensuring the proper lipid composition of the myelin sheath. In MG, QKI regulates phagosome maturation and the expression of inflammatory genes, thus promoting efficient clearance of myelin debris and fostering a permissive environment for remyelination. Reduced QKI expression has been documented in MS and its experimental models. In this context, this review summarizes current evidence positioning QKI as a central regulator of myelin maintenance and regeneration and highlights its potential as a therapeutic target for demyelinating diseases.
髓鞘由中枢神经系统（CNS）中的少突胶质细胞（OLGs）合成，是一种多层结构，能够实现动作电位的快速传导，并为其环绕的轴突提供代谢支持。在慢性神经疾病多发性硬化症（MS）中，髓鞘膜成为免疫介导攻击的目标。这些攻击触发炎性细胞因子的释放并激活小胶质细胞（MG）和星形胶质细胞，导致严重的脱髓鞘和神经变性。颤抖蛋白（QKI）是一种多功能RNA结合蛋白，通过调节神经胶质细胞中的RNA代谢和脂质稳态，在中枢神经系统髓鞘形成中起关键作用。通过其主要异构体QKI-5、QKI-6和QKI-7，QKI协调少突胶质细胞中重要的转录后过程，包括关键髓鞘转录本的剪接、稳定性、核输出和局部翻译。QKI缺乏会改变许多参与轴突包裹和髓鞘形成途径的基因的表达，如髓鞘碱性蛋白（MBP）、蛋白脂蛋白1（PLP1）、髓鞘相关糖蛋白（MAG）和神经束膜蛋白155（Nfasc155）。QKI还通过作为转录共激活因子来调节胆固醇和脂肪酸的生物合成，确保髓鞘具有适当的脂质组成。在小胶质细胞中，QKI调节吞噬体成熟和炎性基因的表达，从而促进髓鞘碎片的有效清除，并为髓鞘再生营造有利环境。在多发性硬化症及其实验模型中，已有QKI表达降低的记录。在此背景下，本综述总结了当前将QKI定位为髓鞘维持和再生的核心调节因子的证据，并强调了其作为脱髓鞘疾病治疗靶点的潜力。
