Endoplasmic reticulum stress in disorders of myelinating cells

Abstract

Myelinating cells, oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system produce an enormous amount of plasma membrane during the myelination process, making them particularly susceptible to disruptions of the secretory pathway. Endoplasmic reticulum stress, initiated by the accumulation of unfolded or misfolded proteins, activates the unfolded protein response, which adapts cells to the stress. If this adaptive response is insufficient, the unfolded protein response activates an apoptotic program to eliminate the affected cells. Recent observations suggest that endoplasmic reticulum stress in myelinating cells is important in the pathogenesis of various disorders of myelin, including Charcot-Marie-Tooth disease, Pelizaeus-Merzbacher disease and Vanishing White Matter Disease, as well as in the most common myelin disorder, multiple sclerosis. A better understanding of endoplasmic reticulum stress in myelinating cells has laid the groundwork for the design of new therapeutic strategies for promoting myelinating cell survival in these disorders.

Figure 1. Oligodendrocyte and myelin

Oligodendrocytes produce as an extension of their plasma membrane vast amounts of myelin; a unique, lipid-rich, multilamellar sheath that wraps axons in the CNS. The secretory pathways for protein and lipid, including rough ER, smooth ER and Glogi apparatus, are well developed in oligodendrocytes. Evidence is accumulating that oligodendrocytes, as well as their PNS counterpart Schwann cells, rank among the cells that are most sensitive to the disruption of the secretory pathway.

Figure 2. The UPR pathway in eukaryotic cells

ER stress triggers PERK dimerization and auto-phosphorylation. Activated PERK attenuates protein biosynthesis by phosphorylating eIF2α. Phosphorylated eIF2α also activates transcription factor ATF4, which enhances the stress-induced expression of numerous cytoprotective genes. Additionally, ATF4 increases the expression of CHOP, which induces GADD34 expression. GAAD34 binds to PP1 and forms the GADD34-PP1 complex that specifically dephosphorylates eIF2α. ER stress also triggers IRE1dimerization and auto-phosphorylation. Activation of IRE1 initiates the splicing of XBP1 mRNA, producing an active transcription factor sXBP-1. Additionally, ATF6 becomes an active transcription factor by transiting to the Golgi complex, where it is cleaved by the proteases S1P and S2P. The activation of IRE1 signaling and the cleavage of ATF6 promote ER expansion and the expression of ER-localized chaperones. In multicellular organisms, if these adaptive responses are not sufficient to resolve the folding problems in the ER, the UPR will trigger an apoptotic program, such as activation of caspase 12 or CHOP, to eliminate the cells.