The beneficial role of autophagy in multiple sclerosis: Yes or No?

Abstract

Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS) due to an increase of abnormal peripherally auto-reactive T lymphocytes which elicit autoimmunity. The main pathophysiology of MS is myelin sheath damage by immune cells and a defect in the generation of myelin by oligodendrocytes. Macroautophagy/autophagy is a critical degradation process that eliminates dysfunctional or superfluous cellular components. Autophagy has the property of a double-edged sword in MS in that it may have both beneficial and detrimental effects on MS neuropathology. Therefore, this review illustrates the protective and harmful effects of autophagy with regard to this disease. Autophagy prevents the progression of MS by reducing oxidative stress and inflammatory disorders. In contrast, over-activated autophagy is associated with the progression of MS neuropathology and in this case the use of autophagy inhibitors may alleviate the pathogenesis of MS. Furthermore, autophagy provokes the activation of different immune and supporting cells that play an intricate role in the pathogenesis of MS. Autophagy functions in the modulation of MS neuropathology by regulating cell proliferation related to demyelination and remyelination. Autophagy enhances remyelination by increasing the activity of oligodendrocytes, and astrocytes. However, autophagy induces demyelination by activating microglia and T cells. In conclusion, specific autophagic activators of oligodendrocytes, and astrocytes, and specific autophagic inhibitors of dendritic cells (DCs), microglia and T cells induce protective effects against the pathogenesis of MS.Abbreviations: ALS: amyotrophic lateral sclerosis; APCs: antigen-presenting cells; BBB: blood-brain barrier; CSF: cerebrospinal fluid; CNS: central nervous system; DCs: dendritic cells; EAE: experimental autoimmune encephalomyelitis; ER: endoplasmic reticulum; LAP: LC3-associated phagocytosis; MS: multiple sclerosis; NCA: non-canonical autophagy; OCBs: oligoclonal bands; PBMCs: peripheral blood mononuclear cells; PD: Parkinson disease; ROS: reactive oxygen species; UPR: unfolded protein response.

Keywords: Astrocytes; autophagy; disease; multiple sclerosis; oligodendrocytes.

Figure 1.

Molecular aspects of autophagy. Rapamycin and torin 1 initiate signaling for the formation of autophagosomes through inhibition of MTOR. ULK-101 inhibits initiation of autophagy through inhibition of the ULK1 kinase complex. The class III phosphatidylinositol 3-kinase complex generates PtdIns3P as part of nucleation; this step is activated by BRD1991 and inhibited by SAR405 and compound 19. Expansion and closure of the phagophore is activated by AUTACs and inhibited by autogramin-2. Autophagosomes fuse with the lysosomes, and this process is inhibited by bafilomycin A₁, verucopeptin and autoquin. LYTACs (lysosome targeting chimera), EN6 (an activator of lysosomal vacuolar-type H⁺-translocating ATPase; V-ATPase), and MA6-93 are activators that enhance binding of lysosomes to autophagosomes.

Figure 2.

Autophagy in PD. Impairment of autophagy enhances transcription of MAPT/tau and SNCA which also enhances oligomerization and aggregation of pathogenic SNCA.

Figure 3.

Autophagy in AD. Transport and maturation of autophagosomes are impaired in AD leading to defects in the elimination of oxidative stress.

Figure 4.

Autophagy in amyotrophic lateral sclerosis. Autophagy receptors such as OPTN recognize diverse ubiquitin-conjugated autophagy substrates. ALS-linked pathological mutations in OPTN disrupt such substrate recognition, resulting in a failure to load the ubiquitinated substrates into the phagophore and consequent accumulation of protein aggregates and damaged mitochondria. Movement of the autophagosome along a microtubule track to a lysosome is dependent on the dynactin-dynein complex. Mutations of dynactin or dynein impair this trafficking of the autophagosome. Furthermore, ALS-associated mutation may also impair this process by targeting the dynactin-dynein complex. Fusion between the autophagosome and a lysosome may be disrupted by rare ALS-associated mutations; ALS-linked mutations have been found in the genes encoding the indicated proteins (in bold red font).

Figure 5.

Autophagy in multiple sclerosis. Reactive oxygen species (ROS) produced by activated astrocytes and microglia inhibit oligodendrocytes and the development of MS due to demyelination. Activated astrocytes and microglia enhance the release of pro-inflammatory cytokines, IL1B (interleukin 1 beta), TNF (tumor necrosis factor) and IFNG (interferon gamma).