Abstract: DNA damage has been linked to neuropathology. Diverse DNA damage response (DDR) pathways help preserve DNA integrity in the nervous system during both the developmental and mature stages. Mutations of factors in various signaling pathways responsive to different types of DNA damage have been associated with developmental syndromes with neurological symptoms (McKinnon, 2009; Araújo and Kuraoka, 2019; Khokhlova et al., 2020). For example, mutations in a single gene encoding ataxia-telangiectasia mutated (ATM), which is activated by DNA double-strand breaks for checkpoint initiation, can lead to ataxia telangiectasia (McKinnon, 2004). It is believed that neuropathology can result from cellular DNA damage, or even DNA damage within the mitochondria, as has been shown to correlate with aging and Parkinson’s disease (Bender et al., 2006). However, attributing all the mechanisms underlying neurological diseases caused by DDR gene deficiencies to the accumulation of genetic alterations is an oversimplification. In particular, non-canonical DDRs have exhibited examples of uncoupling of upstream triggers (DNA damage) and downstream events. Other than single/double-strand breaks of DNA, for instance, telomere maintenance and oxidative stress in cells can also activate DDR (Burgess and Misteli, 2015). The consequences of DDR have been typically characterized as cell-cycle arrest, expression of repair genes, apoptosis, etc. However, the specific effects of DDR pathway activation in various types of cells, especially the terminally differentiated cells, warrant further exploration. Whether the DDR machinery can function beyond its traditional role remains an open question.