Disproportionate Expression of ATM in Cerebellar Cortex During Human Neurodevelopment

Deacon, Simon; Dalleywater, William; Peat, Charles; Paine, Simon M.L.; Dineen, Rob A.

Abstract

Cerebellar neurodegeneration is a classical feature of ataxia telangiectasia (A-T), an autosomal recessive condition caused by loss-of-function mutation of the ATM gene, a gene with multiple regulatory functions. The increased vulnerability of cerebellar neurones to degeneration compared to cerebral neuronal populations in individuals with ataxia telangiectasia implies a specific importance of intact ATM function in the cerebellum. We hypothesised that there would be elevated transcription of ATM in the cerebellar cortex relative to ATM expression in other grey matter regions during neurodevelopment in individuals without A-T. Using ATM transcription data from the BrainSpan Atlas of the Developing Human Brain, we demonstrate a rapid increase in cerebellar ATM expression relative to expression in other brain regions during gestation and remaining elevated during early childhood, a period corresponding to the emergence of cerebellar neurodegeneration in ataxia telangiectasia patients. We then used gene ontology analysis to identify the biological processes represented in the genes correlated with cerebellar ATM expression. This analysis demonstrated that multiple processes are associated with expression of ATM in the cerebellum, including cellular respiration, mitochondrial function, histone methylation, and cell-cycle regulation, alongside its canonical role in DNA double-strand break repair. Thus, the enhanced expression of ATM in the cerebellum during early development may be related to the specific energetic demands of the cerebellum and its role as a regulator of these processes.

• Journal Article Type: Article
• Acceptance Date: Apr 20, 2023
• Online Publication Date: Apr 29, 2023
• Publication Date: 2024-04
• Deposit Date: Apr 24, 2023
• Publicly Available Date: Apr 30, 2024
• Journal: Cerebellum
• Print ISSN: 1473-4222
• Electronic ISSN: 1473-4230
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 23
• Issue: 2
• Pages: 502-511
• DOI: https://doi.org/10.1007/s12311-023-01560-2
• Keywords: Cerebellum, Ataxia telangiectasia, Transcriptome, Gene ontology
• Public URL: https://nottingham-repository.worktribe.com/output/19995218
• Publisher URL: https://link.springer.com/article/10.1007/s12311-023-01560-2
• Additional Information: Accepted: 20 April 2023; First Online: 29 April 2023; : ; : The data used in this analysis was publicly available in BrainSpan Atlas of the Developing Human Brain, which provides de-identified transcriptomic data from post-mortem samples. No additional ethical approval was required for use of this open-access dataset.; : The authors declare no competing interests.