Evaluating autophagy in the CNS: implications for multiple sclerosis

Multiple sclerosis (MS) is a complex auto-immune, neurodegenerative disorder of the central nervous system (CNS), which involves a range of CNS and immune cells. Autophagy is an intracellular degradation process that is essential to maintain cellular homeostasis. Dysregulation of autophagy leads to the accumulation of cytotoxic aggregates and aggravates immune responses. In this dissertation, we exploited primary rat glial cells, MS mouse models, and post-mortem human MS brain tissue, to gather new insights into the involvement of autophagy in the pathological CNS features over the course of MS.
Chapter 2 showed increased mTORC1 activity during the acute phase of EAE development, a model that reflects the autoimmune component of MS, where we proposed that this increase in activity negatively regulates autophagy at both the transcriptional and the translational levels. Chapter 3 uncovered differences in autophagic activity in glial cells when exposed to an inflammatory stimulus and showed that autophagy participates in myelin phagocytosis by microglia. Chapter 4 revealed the involvement of mTORC1 in the remyelination processes after cuprizone-induced demyelination, whereas autophagy might be involved in cuprizone-induced demyelination. Chapter 5 presents the microglia gene expression signature of macaques, where we observed the presence of different autophagy-related genes that were more abundantly expressed in microglia/macrophages compared to other CNS cells.
Together, the data presented in this thesis contribute to our understanding of the role of autophagy in CNS homeostasis and MS disease. In the long-term, these findings may lead to the identification of promising intervention targets to modulate autophagy in disorders associated with the CNS, including MS.