Neurotoxic consequence of microglia promoted inflammation in neurodegenerative disease

Abstract

ATM (ataxia-telangiectasia mutated) is a protein whose function is vital to a cell's DNA damage response (DDR), especially to DNA double strand breaks. Mutations in ATM result in a genetic disease, Ataxia-Telangiectasia (A-T), characterized by cancer predisposition, neurodegeneration, immunodeficiency and inflammatory features in the brain. For my thesis research, I have shown that, the neurological symptom in A-T is highly related to the activation of innate immune system in the brain. Upon immune challenge or in the absence of ATM kinase function, microglia undergo a robust activation that includes an overproduction of cytokines. This creates a pro-inflammatory environment that greatly contributes to the neurodegeneration which is a core symptom of the (A-T) cerebellum. Central to this abnormal activation of microglia in A-T is the finding that ATM dysfunction results in accumulation of cytosolic DNA in a variety of cell types. In microglia, the elevated level of cytoplasmic DNA primes the anti-virus innate immune response via the cytosolic DNA sensor, STING. Knockdown of STING or inhibition of STING activity rescued the inflammatory response, specifically, the overproduction of cytokines. Cytosolic DNA species also works through the AIM2-containing inflammasome to process pro-IL-1β to its active form, IL-1β. My work adds depth to the explanation of the cerebellar neurodegeneration phenotype of A-T. Most A-T patients are diagnosed with a severe immune deficiency due to the arrested development of both B cells and T cells. In this study, I show the problems caused by this failure of the adaptive immune system are compounded by the overreaction of the innate immune system. Brain microglia, the major immune cells of the central nervous system become activated and assume a neurotoxic pro-inflammatory phenotype. This broadens the explanation of the neurodegeneration found in A-T and calls attention to the importance of the microglia-neuron interaction. The present work also pointed out the fundamentality of accumulated cytosolic DNA in triggering the activation of pro-inflammatory pathway in the immune cells. Meanwhile, the evidence for the presence of cytoplasmic DNA in other cell types under different disease condition are also relevant to our understanding of a wider range of neurodegenerative diseases.

Date of Award	2019
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology