Quaking Protein in Myelin Maintenance and Regeneration in the Central Nervous System

Abstract

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.