APEX1 and amyotrophic lateral sclerosis: Similarly, Ref-1/APE1 levels are elevated in the central nervous system of patients with ALS, a disease exhibiting elevated oxidative stress and DNA damage.232 In PD, loss of Ref-1/APE1 function via gene variants suggests it is a risk factor, contributing to increased oxidative stress that leads to loss of dorsal root ganglion (DRG) neurons.233 Ref-1/APE1 is upregulated in cells treated with rotenone234 and MPP+ (1-methyl-4-phenylpyridinium),235 both of which are used to simulate a PD model.