APTX deficiency is associated with altered neuronal differentiation and alternative splicing in patient-derived neurons.
TL;DR
It is demonstrated that AOA1-derived neurons exhibit neurite morphology and maturation defects correlated with the accumulation of DNA single-strand break (SSB) signals, and DNA-damage and PAR signals showed greater DNA-damage and PAR signals together with lower protein-normalized NAD(H) and ATP after genotoxic exposure.
Abstract
Ataxia with oculomotor apraxia type 1 (AOA1), caused by mutations in the DNA repair protein aprataxin (APTX), leads to progressive neurodegeneration. In this study, we established an AOA1 patient-derived induced pluripotent stem cell (iPSC) and a neuronal differentiation model. We demonstrated that AOA1-derived neurons exhibit neurite morphology and maturation defects correlated with the accumulation of DNA single-strand break (SSB) signals. AOA1-derived neurons showed greater DNA-damage and PAR signals together with lower protein-normalized NAD(H) and ATP after genotoxic exposure. These parallel changes are consistent with metabolic stress but do not establish a PARP1-dependent causal pathway. Bulk transcriptomic profiling and alternative splicing (AS) analysis further revealed widespread transcriptomic dysregulation and altered AS events, particularly enriched in neuronal genes essential for neurite development and synaptic function. Collectively, our findings identify neuronal differentiation, DNA-damage, metabolic, and transcriptomic differences in AOA1 patient-derived cultures and motivate composition-controlled and rescue-based studies of APTX function.