Project Details
Projekt
The deubiquitinating enzyme A20 as gate keepers of central nervous system homeostasis
Applicant
Professor Dr. Ari Waisman
Subject Area
Experimental Models for the Understanding of Nervous System Diseases
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 500247271
Lysine-63 ubiquitination is a post-translational modification for a number of intracellular processes, including the activation of the NFkappaB signaling pathway. Removal of these ubiquitin chains is performed by a class of proteases termed deubiquitinating (DUB) enzymes, representing an important mechanism to control NFkappaB activity. We and others have shown that the DUB enzyme A20 regulates the NFkappaB pathway in a variety of immune cells, including T cells, B cells, dendritic cells as well as in different macrophage subsets, including particularly microglia cells. We recently reported A20 to be critical for the function of microglia during steady state, where in the absence of this DUB enzyme, the microglia started to express genes associated with viral infection, which ultimately led to the invasion of the CNS by CD8+ T cells. Furthermore, mice lacking A20 in microglia presented with dysfunctional neuronal networks, which could be corrected by the elimination of the invading T cells. Next to A20, there is another important NFkappaB pathway-relevant DUB enzyme called CYLD. In the frame of the first funding period of this SPP, we could conclusively show that CYLD does not play a role in microglia in steady-state or during CNS autoimmunity. In the second SPP funding period, we plan to further investigate the precise role of A20 during microglia homeostasis and its function during ageing, autoimmunity as well as neurodegeneration. Specifically, we want to analyze how hyper-activation of microglia after A20 deletion leads to neurological dysfunction and modulates the gene expression in neurons and surrounding glial cells. We further plan to investigate precisely the role of Interferon-gamma, as produced by invading T cells, by establishing novel genetic mouse models targeting producers as well as responders to this cytokine in the context of A20-deficient microglia. Next, we will test the mice with microglial hyper-activation for the development, progression, and resolution of CNS autoimmunity, specifically in the EAE model. Finally, we aim to analyze the possible role for microglial regulation through A20 in the process of ageing, using both mouse models and human post mortem material from healthy (aged) as well as Alzheimer’s Disease patients. Together, our proposed experiments aim to evaluate A20 as potential regulator of microglia activity and function at steady state as well as during CNS inflammation associated with autoimmunity or ageing. Ultimately, this should identify A20 as target for manipulation to further study these physiological and pathological processes.
DFG Programme
Priority Programmes
