Neuronal pathogenic mechanisms in ataxia telangiectasia disease

Ataxia telangiectasia (A-T) is caused by mutations in the ATM gene, with primary symptoms that arise in early childhood. The literature unequivocally presents a wide array of studies on the basis of the disease, but the exact mechanisms leading to neurodegeneration are still subject of investigation. The focal point of this work is to explore further the neuropathogenesis of A-T by analyzing ATM’s role in mitochondrial function, ER-mitochondrial signaling, and the autophagy-lysosomal pathway. Recently, it was discovered that ATM activation could lead to the phosphorylation of the transcription factor NRF1 at residue T259 during oxidative conditions. Results revealed that the lack of ATM function often leads to the death of cerebellar cells, which cannot sustain their neuronal activity due to ATP shortage. Moreover, it examines the sensitivity of A-T cells to glycolysis inhibition by focusing on the disrupted endoplasmic reticulum-mitochondria tethering which impacts on calcium homeostasis, mitochondrial fusion processes and mitophagy. It also underlines how an aberrant modulation of autophagy, lysosomal trafficking and glucose uptake can impair synaptic vesicle function and neurotransmission. It deepens insight into how ATM association with ATP6V1A, DYNLL1 and SLC2A4 participates in the regulation of these cellular processes. These data all together highlight how the involvement of ATM is essential for neuronal survival. Understanding of the underlying mechanisms could alleviate the neurodegenerative impact of A-T and improve patient symptoms.