The role of autophagy in the pathogenesis and treatment of multiple sclerosis

Abstract

Autophagy is a crucial cellular process responsible for the degradation and recycling of damaged or unnecessary components, maintaining cellular homeostasis and protecting against stress. Dysregulation of autophagy has been implicated in a variety of neurodegenerative diseases, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Various types of autophagy exist, each with distinct mechanisms, such as macroautophagy, mitophagy, lipophagy, and chaperone-mediated autophagy. These processes are essential for the removal of toxic substrates like protein aggregates and dysfunctional mitochondria, which are vital for neuronal health. In neurodegenerative diseases, the impairment of these clearance mechanisms leads to the accumulation of harmful substances, which accelerate disease progression. Modulating autophagy has emerged as a promising therapeutic strategy, with ongoing studies investigating molecules that can either stimulate or regulate this process. However, despite its potential, significant challenges remain in translating preclinical findings into clinically effective treatments. In this review, we will explore the different types of autophagy, their roles in neurodegenerative diseases, and the therapeutic potential associated with modulating these processes.

Keywords: Multiple sclerosis; autophagy; ferritinophagy; lipophagy; mielinophagy; mitophagy; therapy.

Figure 1.

Molecular mechanism of autophagy. Various stress conditions, such as mitochondrial dysfunction, hypoxia, and starvation, can activate AMPK. In turn, AMPK inhibits MTOR and stimulates the ULK1 complex, promoting phagophore formation. Once the phagophore is formed, the PI3K complex mediates its nucleation and elongation into an autophagosome. LCE-PE, along with the ATG12–ATG5–ATG16L1 complex, plays a crucial role in autophagosome maturation and closure. Finally, the fusion of the autophagosome with the lysosome results in the formation of the autophagolysosome, where engulfed macromolecules undergo degradation. Abbreviations: AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (MTOR), UNC-51-like kinase 1 (ULK1), phosphatidylinositol 3-kinase (PI3K), LC3–phosphatidylethanolamine (LC3-PE), autophagy related 12 (ATG12), autophagy related 5 (ATG5), autophagy related 16 like 1 (ATG16L1). Created with Biorender.

Figure 2.

Selective autophagy pathways in neurodegeneration. Autophagy can function in a highly selective manner, defining distinct pathways depending on the macromolecules or organelles targeted for degradation. Mitophagy is tightly regulated by the PINK1/Parkin axis, where PINK1 facilitates the recruitment of Parkin, an E3 ubiquitin ligase that ubiquitinates OMM proteins. Ubiquitinated OMM proteins are recognized by adaptor proteins, which, in turn, recruit LC3, promoting mitochondrial engulfment into autophagosomes. Myelinophagy is influenced by the p75NTR/AMPK/MTOR axis, where p75NTR and AMPK inhibit MTOR, thereby stimulating myelin-specific autophagy in Schwann cells. Lipophagy regulates intracellular lipid storage. Normally, perilipins are removed by protein-kinase a and the proteasome, allowing LDs to be hydrolyzed into glycerol and cholesterol. These components are recognized by PNPLA2 in conjunction with LC3, facilitating their sequestration into autophagosomes for degradation. Ferritinophagy specifically targets intracellular ferritin, a protein responsible for iron storage. Under conditions of iron imbalance, NCOA4 selectively binds ferritin complex, enabling its transport to autophagosomes for degradation. CMA is responsible for the selective degradation of proteins containing a KFERQ-like motif. This motif is recognized by the constitutive chaperone HSC70, which facilitates the translocation of the protein into the lysosome through LAMP2A. Abbreviations: PTEN-induced kinase 1 (PINK1), outer mitochondrial membrane (OMM), p75 neurotrophin receptor (p75NTR), AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (MTOR), protein-kinase a (PKA), lipid droplets (LDs), patatin-like phospholipase domain-containing 2 (PNPLA2), nuclear receptor coactivator 4 (NCOA4), chaperone-mediated autophagy (CMA), heat shock-cognate protein of 70 kDa (Hsp70), lysosome-associated membrane protein type 2A (LAMP2A). Created with Biorender.

Figure 3.

Dysregulated autophagy in multiple sclerosis: pathological mechanisms. Several autophagy-dependent pathways are involved in MS pathogenesis. Direct axonal damage is caused by the accumulation of dysfunctional mitochondria, leading to excessive production of lactate and ROS. Conversely, increased AMPK activity and enhanced activation of the PINK1/Parkin axis promote overactive mitophagy, which further contributes to axonal injury. Additionally, reduced levels of NCOA4 impair ferritinophagy, resulting in disrupted iron storage and uptake, which further increases ROS production. In oligodendrocytes, elevated ROS levels trigger lipid peroxidation and deterioration of the myelin sheath. In parallel, myelin debris, including myelin-related proteins, are not efficiently cleared due to defective myelinophagy. This persistence of debris activates antigen-presenting cells (APCs), thereby initiating an adaptive autoimmune response. Finally, the neurodegenerative environment is exacerbated by the presence of foamy microglia, cells with impaired lipophagy which accumulate lipid droplets and shift toward a proinflammatory phenotype. Abbreviations: reactive oxygen species (ROS), AMP-activated protein kinase (AMPK), nuclear receptor coactivator 4 (NCOA4). Created with Biorender.