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  2. Inhibition of the cGAS-STING pathway ameliorates the premature senescence hallmarks of Ataxia-Telangiectasia brain organoids

Inhibition of the cGAS-STING pathway ameliorates the premature senescence hallmarks of Ataxia-Telangiectasia brain organoids

  • Aging Cell. 2021 Sep;20(9):e13468. doi: 10.1111/acel.13468.
Julio Aguado 1 Harman K Chaggar 1 Cecilia Gómez-Inclán 1 Mohammed R Shaker 1 Hannah C Leeson 1 Alan Mackay-Sim 2 3 Ernst J Wolvetang 1
Affiliations

Affiliations

  • 1 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Saint Lucia, Queensland, Australia.
  • 2 Department of Neurogenetics, Kolling Institute, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
  • 3 Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia.
Abstract

Ataxia-telangiectasia (A-T) is a genetic disorder caused by the lack of functional ATM kinase. A-T is characterized by chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A-T remains elusive. Here, we utilize human pluripotent stem cell-derived cortical brain organoids to study A-T neuropathology. Mechanistically, we show that the cGAS-STING pathway is required for the recognition of micronuclei and induction of a senescence-associated secretory phenotype (SASP) in A-T olfactory neurosphere-derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self-DNA-triggered SASP expression in A-T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A-T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A-T and constitutes a novel therapeutic target for treating neuropathology in A-T patients.

Keywords

Ataxia-Telangiectasia; brain aging; brain organoids; cGAS-STING signalling; cellular senescence; neurodegeneration.

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