Disproportionate Expression of ATM in Cerebellar Cortex During Human Neurodevelopment

Abstract

AbstractCerebellar neurodegeneration is a classical feature of ataxia telangiectasia (A-T), an autosomal recessive condition caused by loss-of-function mutation of theATMgene, 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 intactATMfunction in the cerebellum. We hypothesised that there would be elevated transcription ofATMin the cerebellar cortex relative toATMexpression in other grey matter regions during neurodevelopment in individuals without A-T. UsingATMtranscription data from the BrainSpan Atlas of the Developing Human Brain, we demonstrate a rapid increase in cerebellarATMexpression 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 cerebellarATMexpression. This analysis demonstrated that multiple processes are associated with expression ofATMin 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 ofATMin 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.