Autophagy in Myelinating Glia

Abstract

Autophagy is the cellular process involved in transportation and degradation of membrane, proteins, pathogens, and organelles. This fundamental cellular process is vital in development, plasticity, and response to disease and injury. Compared with neurons, little information is available on autophagy in glia, but it is paramount for glia to perform their critical responses to nervous system disease and injury, including active tissue remodeling and phagocytosis. In myelinating glia, autophagy has expanded roles, particularly in phagocytosis of mature myelin and in generating the vast amounts of membrane proteins and lipids that must be transported to form new myelin. Notably, autophagy plays important roles in removing excess cytoplasm to promote myelin compaction and development of oligodendrocytes, as well as in remyelination by Schwann cells after nerve trauma. This review summarizes the cell biology of autophagy, detailing the major pathways and proteins involved, as well as the roles of autophagy in Schwann cells and oligodendrocytes in development, plasticity, and diseases in which myelin is affected. This includes traumatic brain injury, Alexander's disease, Alzheimer's disease, hypoxia, multiple sclerosis, hereditary spastic paraplegia, and others. Promising areas for future research are highlighted.

Figure 1.

Schematic representation of autophagic pathway. Cellular stress, such as amino acid starvation, targets the ULK1 complex, which then phosphorylates the PI3KC3. This triggers local phosphatidylinositol-3-phosphate (PI3P) production and nucleation of the omegasome. PI3P effectors, such as WIPI2, are then recruited, and interact with the ATG-7-ATG12-ATG5-ATG16L1-ATG3 LC3B-conjugation system. This complex, through ATG3, mediates phosphatidylethanolamine (PE) lipidation of ATG8 family proteins (e.g., LC3B), enabling their recruitment to the phagophore membrane. Membranes contributing the phagophore elongation can have different cellular origins, including recycling endosomes, mitochondria, and ATG9A-containing vesicles exported through AP-4. In selective autophagy, lipidated LC3B-II is critical for sequestration of cytosolic poly-ubiquitylated (Ub) aggregates through receptors, such as p62 and NBR1. The fusion of the mature, sealed, double-membrane autophagosome with lysosomes is mediated by SNARE and HOPS complex. Lysosomal hydrolases and proteases can then degrade the autophagic cargo and nutrients, making lipids and amino acids available for reuse in the cell.

Figure 2.

Autophagy protein expression in oligodendrocyte lineage cells. Cells are premyelinating oligodendrocyte lineage cells cultured from P4 WT rats and plated in growth medium. A, Transcription factor Olig2 (green) for oligodendroglia, adaptor protein 4 (red) and DAPI (blue) for nuclei. B, Transcription factor Olig2 (red), autophagy protein ATG9A (red), and DAPI (blue).