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The DNA repair enzyme, aprataxin, plays a role in innate immune signaling.

Lookup NU author(s): Dr Louise Pease, Rebekah Scanlan, Dr Daryl Shanley



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Ataxia with oculomotor apraxia type 1 (AOA1) is a progressive neurodegenerative disorder characterized by a gradual loss of coordination of hand movements, speech, and eye movements. AOA1 is caused by an inactivation mutation in the APTX gene. APTX resolves abortive DNA ligation intermediates. APTX deficiency may lead to the accumulation of 5’-AMP termini, especially in the mitochondrial genome. The consequences of APTX deficiency includes impaired mitochondrial function, increased DNA single-strand breaks, elevated reactive oxygen species production, and altered mitochondrial morphology. All of these processes can cause misplacement of nuclear and mitochondrial DNA, which can activate innate immune sensors to elicit an inflammatory response. This study explores the impact of APTX knockout in microglial cells, the immune cells of the brain. RNA-seq analysis revealed significant differences in the transcriptomes of wild-type and APTX knockout cells, especially in response to viral infections and innate immune pathways. Specifically, genes and proteins involved in the cGAS-STING and RIG-I/MAVS pathways were downregulated in APTX knockout cells, which suggests an impaired immune response to cytosolic DNA and RNA. The clinical relevance of these findings was supported by analyzing publicly available RNA-seq data from AOA1 patient cell lines. Comparisons between APTX-deficient patient cells and healthy control cells also revealed altered immune responses and dysregulated DNA- and RNA-sensing pathways in the patient cells. Overall, this study highlights the critical role of APTX in regulating innate immunity, particularly in DNA- and RNA-sensing pathways. Our findings contribute to a better understanding of the underlying molecular mechanisms of AOA1 pathology and highlights potential therapeutic targets for this disease.

Publication metadata

Author(s): Madsen HB, Pease LI, Scanlan RL, Akbari M, Rasmussen LJ, Shanley DP, Bohr VA

Publication type: Article

Publication status: Published

Journal: Frontiers in Aging Neuroscience

Year: 2023

Volume: 15

Online publication date: 15/12/2023

Acceptance date: 20/11/2023

Date deposited: 08/03/2024

ISSN (electronic): 1663-4365

Publisher: Frontiers Research Foundation


DOI: 10.3389/fnagi.2023.1290681

PubMed id: 38161589


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Funder referenceFunder name
NNF17OC0027812Novo Nordisk Foundation
Novo Nordisk Foundation