DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Ataxia Telangiectasia (A-T) is a neurodegenerative disorder caused by mutations in the ATM kinase, crucial for DNA damage response.
• The specific mechanisms rendering neurons vulnerable to ATM loss are not fully understood.

Purpose of the Study:

• To investigate if DNA-Topoisomerase 1 adducts (Top1ccs) accumulation in A-T impairs transcription elongation.
• To determine if ATM deficiency affects neuronal activity-induced immediate early genes (IEGs) expression.

Main Methods:

• Utilized human induced pluripotent stem cell (iPSC)-derived neurons.
• Assessed DNA damage response (DDR) and gene expression using techniques including nascent RNA sequencing.
• Stimulated neuronal activity via glutamate receptors and KCl depolarization.

Main Results:

• Top1cc trapping induced an ATM-dependent DDR and an ATM-independent IEG induction, with repression of long genes.
• Transcriptional elongation and recovery rates were unaffected by gene length or ATM status.
• Neuronal activity triggered DDR and IEG expression independently of ATM.
• A-T neurons exhibited downregulation of specific genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) vital for central nervous system function.

Conclusions:

• ATM deficiency in neurons may lead to neurodegeneration through impaired regulation of specific genes involved in CNS development and maintenance.
• Neuronal activity-induced IEG expression and DDR are largely independent of ATM status.