Microglial Munchies: Exploring Lysosomal Dysfunction in CNS Immunopathology with a Twist of Food for Thought

Le 12 avril 2024 à 14h00 Séminaire

Microglia, the tissue-resident macrophages of the CNS parenchyma, play pivotal roles in maintaining tissue homeostasis, defending against pathogens, and orchestrating CNS development. Their phagocytic activity, essential for clearing dying cells and protein aggregates, with efficient lysosomal degradation of cargo, are key for microglia functions in the CNS and the maintenance of tissue homeostasis. In neurodegenerative diseases, including Alzheimer's Disease, microglia display disease-specific activation, exemplified by the "disease-associated microglia" (DAM) signature with induction of many different hallmark genes including Cathepsin-D (Ctsd), an aspartic endopeptidase. Loss of function mutations in CTSD cause a severe form of lysosomal storage disease: ceroid neuronal lipofuscinosis type 10 (NCL-10) which is characterized by severe neurodegeneration. Ctsd-deficient mice recapitulate NCL-10 features, such as neuronal loss and subsequent microgliosis and astrogliosis. Even though it was suggested that loss of Ctsd in neurons is the main contributor to the disease pathology, replacement therapy approaches in neurons failed to cure or block disease progression in mice. Furthermore, it remained so far unclear which contribution microglia have in the NCL-10 disease pathology and if they are potential key drivers of disease progression. Within this study, we set out to explore the consequences of Ctsd-deficiency in microglia on their homeostatic function and the potential implication of microglia in the histopathological changes seen in patients with NCL-10.