THESIS
2019
xiii, 165 pages : illustrations (some color) ; 30 cm
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. Cent...[
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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.
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