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Mechanisms for maintaining ER protein homeostasis in myelinating cells

维持髓鞘细胞内质网蛋白稳态的机制

基本信息

批准号：
10350658
负责人：
Wensheng Lin
金额：
$ 33.69万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-15 至 2025-02-28
项目状态：
未结题

项目摘要

Project Summary/Abstract: Myelinating cells, oligodendrocytes (OLs) in the CNS and Schwann cells (SCs) in the PNS, produce a vast amount of myelin sheath. Actively myelinating OLs and SCs must produce enormous amounts of myelin proteins to assemble myelin sheath during development. Mature OLs and SCs in adults need to produce a substantial amount of myelin proteins to maintain myelin structure homeostasis. Myelin proteins are synthesized, modified, and folded in the endoplasmic reticulum (ER). Maintaining ER protein homeostasis is essential and necessary for the function of myelinating cells. Currently available data indicate that actively myelinating OLs and SCs are more sensitive to disruption of ER protein homeostasis than mature OLs and SCs, due to the rate of myelin protein production. Nevertheless, the mechanisms by which myelinating cells maintain ER protein homeostasis remain unexplored. Misfolded/unfolded proteins in the ER are detected and degraded by a process known as ER-associated degradation (ERAD). In response to ER stress, activation of the unfolded protein response (UPR), which comprises three parallel signaling pathways PERK, IRE1, and ATF6α, restores ER protein homeostasis by facilitating protein folding, attenuating protein translation, and enhancing ERAD. Deletion of either PERK or ATF6α does not affect myelinating cells under normal conditions. Surprisingly, our preliminary results showed that double deletion of PERK and ATF6α in myelinating cells led to late-onset dysmyelination in the CNS of adult mice. Both PERK activation and ATF6α activation stimulates the expression of genes related to the Sel1L-Hrd1 complex, the best-characterized ERAD machinery. Intriguingly, our preliminary observation showed that Sel1L inactivation specifically in myelinating cells led to adult-onset dysmyelination in mice. Data indicate that overexpression of PLP, the most abundant myelin protein in the CNS and a substrate of ERAD, leads to soma retention of PLP in OLs, resulting in adult-onset dysmyelination in the CNS. Importantly, our preliminary data showed that both Sel1L inactivation and inactivation of PERK and ATF6α induced soma retention of PLP in OLs. Thus, in this proposal, we will test the hypothesis that the UPR is required for maintaining ER protein homeostasis and the viability and function of mature OLs in adults by regulating ERAD of PLP. In Aim 1, we will demonstrate that inactivation of PERK and ATF6α impairs the viability and function of mature OLs in adult mice. In Aim 2, we will demonstrate that Sel1L inactivation impairs the viability and function of mature OLs and SCs in adult mice. In Aim 3, we will determine if Sel1L inactivation compromises the viability and function of mature OLs through impairment of ERAD of PLP and subsequent soma retention of PLP. This work will uncover a mechanism responsible for maintaining ER protein homeostasis in mature OLs. The knowledge gained from these studies will advance our understanding of the biology of myelinating cells.

项目总结/文摘: