Autophagy in white matter disorders of the CNS: mechanisms and therapeutic opportunities

Abstract

Autophagy is a constitutive process that degrades, recycles and clears damaged proteins or organelles, yet, despite activation of this pathway, abnormal proteins accumulate in neurons in neurodegenerative diseases and in oligodendrocytes in white matter disorders. Here, we discuss the role of autophagy in white matter disorders, including neurotropic infections, inflammatory diseases such as multiple sclerosis, and in hereditary metabolic disorders and acquired toxic‐metabolic disorders. Once triggered due to cell stress, autophagy can enhance cell survival or cell death that may contribute to oligodendrocyte damage and myelin loss in white matter diseases. For some disorders, the mechanisms leading to myelin loss are clear, whereas the aetiological agent and pathological mechanisms are unknown for other myelin disorders, although emerging studies indicate that a common mechanism underlying these disorders is dysregulation of autophagic pathways. In this review we discuss the alterations in the autophagic process in white matter disorders and the potential use of autophagy‐modulating agents as therapeutic approaches in these pathological conditions. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Development and validation of prognostic model based on the analysis of autophagy-related genes in colon cancer

“…Depending on the environment, autophagy acts as a dual part in cancer [ 6 ], possibly reducing the viability of tumor cells or as a cytoprotective mechanism [ 7 ]. In some situations, autophagy can produce nutrients to provide energy for cells by constitutively eliminating defective proteins and organelles [ 8 ]. Conversely, autophagy can trigger cell death under certain conditions, such as over-regulation of autophagy or long-term exposure to autophagy [ 8 ].…”

“…In some situations, autophagy can produce nutrients to provide energy for cells by constitutively eliminating defective proteins and organelles [ 8 ]. Conversely, autophagy can trigger cell death under certain conditions, such as over-regulation of autophagy or long-term exposure to autophagy [ 8 ]. Autophagy has played an important intermediary role in terms of resistance to radiation, chemotherapy, and targeted agents [ 9 , 10 ].…”

Rapamycin Alleviates Protein Aggregates, Reduces Neuroinflammation, and Rescues Demyelination in Globoid Cell Leukodystrophy

“…Several pieces of evidence indicated that disturbed autophagy plays a pivotal role in the pathogenesis of white matter disorders and therapeutics targeting autophagy may be a promising strategy [ 33 ]. Our previous studies have demonstrated the fundamental aspect of GLD in that both impaired autophagy and dysfunction of UPS lead to the broad deposition of p62- and ubiquitin-aggregates resulting in the death of oligodendrocytes in the central nervous system [ 14 ].…”

Local cholesterol metabolism orchestrates remyelination

“…Microglia/macrophages show the highest phagocytic activity, but also astrocytes contribute to myelin clearance [38]. The internalization and turnover of myelin lipids and proteins in these cells, which involve autophagic processes [39][40][41][42], then contributes to the resolution of neuroinflammation [43,44]. As myelin debris and a proinflammatory environment strongly inhibit oligodendroglial differentiation [45], the lysosomal degradation of myelin lipids and proteins in phagocytes is a prerequisite for repair of demyelinated lesions.…”