Abstract
Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.
Highlights
Myelination in the central nervous system (CNS) by oligodendrocytes (OLs) is essential for rapid impulse conduction and normal brain function [1, 2]
Oligodendrocyte progenitor cells (OPCs) exist in the adult mouse CNS and can differentiate into mature OLs to mediate adult myelinogenesis, which is important for remyelination following demyelinating injury [19, 20]
Expression of Sec13 and Sec31A was significantly upregulated following demyelination, and it was substantially expressed in the OL lineage as indicated by Olig2-expressing cells (Figure 1, A–D), suggesting that protein trafficking mediated by complex II (COPII) may play important roles during the remyelination process
Summary
Myelination in the central nervous system (CNS) by oligodendrocytes (OLs) is essential for rapid impulse conduction and normal brain function [1, 2]. Disrupted myelin repair impairs nerve conduction and contributes to neurological dysfunction, axon degeneration, and progression of diseases such as multiple sclerosis (MS) and leukodystrophies [3]. Oligodendrocyte progenitor cells (OPCs) are present in demyelinated regions of patients with MS, and there is evidence of impaired OL differentiation [4]. Understanding how OL differentiation and remyelination are regulated has implications for proper brain functions and therapy in demyelinating diseases. Dysregulation of COPII components has been reported to inhibit protein secretion and affect cell differentiation, function, and homeostasis [7–12]. A comprehensive understanding of the physiological function and the underlying mechanism of COPII components in OL differentiation and myelination is missing
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