Consistent with the essential role of PNKP-mediated classical NHEJ repair in postmitotic neurons (Chatterjee et al., 2015; Chakraborty et al., 2016), higher level of DNA damage accumulates in affected brain regions of SCA3 patients and mice model (Gao et al., 2019; Chakraborty et al., 2020). This evidence concerns the gene PNKP and Machado-Joseph disease.