ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neurodegeneration
Volume 19 - 2025 | doi: 10.3389/fnins.2025.1636787
This article is part of the Research TopicBiomarkers for the identification of effective treatments for neurodegenerative diseaseView all articles
NETSseq Reveals Inflammatory and Aging Mechanisms in Distinct Cell Types Driving Cerebellar Decline in Ataxia Telangiectasia
Provisionally accepted
Giuliano G Stirparo*
Xiao XuToni ThompsonKeith PageJenna RM HarveyDavid CadwalladrJason LawrenceRussell J BurleyJoel JuvvanapudiMegan RobertsDaniel F BarkerVictoria MulliganChloe SherlockMarina Lizio
Louisa ChristieMani MudaliarSteven SheardownBrad MargusCraig ThompsonLouise DicksonNicola L BriceMark B CarltonJustin AC PowellLee A Dawson- Cerevance Ltd, Cambridge, United Kingdom
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Ataxia-telangiectasia (A-T) is a rare, autosomal recessive, multisystem disorder caused by mutations in the Ataxia-Telangiectasia Mutated (ATM) gene and is characterized by a devastating and progressive neurological pathology. The cellular and molecular changes driving the neurological abnormalities associated with A-T are not well understood. Here, we applied our proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform to investigate changes in cell type composition and gene expression in human cerebellar post-mortem tissue from A-T and control donors. We found dysregulation in neurotransmitter signaling in granule neurons, potentially underlying the impaired motor coordination in A-T. Astrocytes and microglia have evidence of accelerated aging, with astrocytes being characterized by neurotoxic signatures, while microglia showed activation of DNA damage response pathways. Compared to single-nuclei technologies, NETSseq provided a more robust detection of genes with low abundance, a higher cell type specific expression pattern, and significantly lower levels of cross-contamination. These findings highlight the importance of NETSseq as a resource for investigating mechanisms and biological processes associated with disease, providing high-sensitivity, cell-specific insights to advance targeted therapies for neurodegenerative diseases.
Keywords: Ataxia Telangiectasia, NETSseq, neurodegeneration, Inflammation, Aging, ATR pathway
Received: 28 May 2025; Accepted: 22 Jul 2025.
Copyright: © 2025 Stirparo, Xu, Thompson, Page, Harvey, Cadwalladr, Lawrence, Burley, Juvvanapudi, Roberts, Barker, Mulligan, Sherlock, Lizio, Christie, Mudaliar, Sheardown, Margus, Thompson, Dickson, Brice, Carlton, Powell and Dawson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Giuliano G Stirparo, Cerevance Ltd, Cambridge, United Kingdom
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