Stone Sarrabeth, Wu Shuangchan, Nave Klaus-Armin, Lin Wensheng
Department of Neuroscience and.
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota, USA.
JCI Insight. 2020 Mar 12;5(5):132364. doi: 10.1172/jci.insight.132364.
Maintaining cellular proteostasis is essential for oligodendrocyte viability and function; however, its underlying mechanisms remain unexplored. Unfolded protein response (UPR), which comprises 3 parallel branches, inositol requiring enzyme 1 (IRE1), pancreatic ER kinase (PERK), and activating transcription factor 6α (ATF6α), is a major mechanism that maintains cellular proteostasis by facilitating protein folding, attenuating protein translation, and enhancing autophagy and ER-associated degradation. Here we report that impaired UPR in oligodendrocytes via deletion of PERK and ATF6α did not affect developmental myelination but caused late-onset mature oligodendrocyte dysfunction and death in young adult mice. The detrimental effects of the impaired UPR on mature oligodendrocytes were accompanied by autophagy impairment and intracellular proteolipid protein (PLP) accumulation and were rescued by PLP deletion. Data indicate that PLP was degraded by autophagy and that intracellular PLP accumulation was cytotoxic to oligodendrocytes. Thus, these findings imply that the UPR is required for maintaining cellular proteostasis and the viability and function of mature oligodendrocytes in adults by regulating autophagy of PLP.
维持细胞蛋白质稳态对于少突胶质细胞的存活和功能至关重要；然而，其潜在机制仍未得到探索。未折叠蛋白反应（UPR）由3个平行分支组成，即肌醇需求酶1（IRE1）、胰腺内质网激酶（PERK）和激活转录因子6α（ATF6α），是一种通过促进蛋白质折叠、减弱蛋白质翻译以及增强自噬和内质网相关降解来维持细胞蛋白质稳态的主要机制。在此我们报告，通过缺失PERK和ATF6α使少突胶质细胞中的UPR受损，并不影响发育性髓鞘形成，但会导致年轻成年小鼠出现迟发性成熟少突胶质细胞功能障碍和死亡。UPR受损对成熟少突胶质细胞的有害影响伴随着自噬损伤和细胞内蛋白脂蛋白（PLP）积累，而通过缺失PLP可挽救这些影响。数据表明PLP通过自噬降解，并且细胞内PLP积累对少突胶质细胞具有细胞毒性。因此，这些发现意味着UPR通过调节PLP的自噬来维持细胞蛋白质稳态以及成年期成熟少突胶质细胞的存活和功能。
