Abstract: Mutations in the gene encoding SETX, also known as Senataxin, are mainly linked to two distinct neurodegenerative diseases, a cerebellar ataxia known as oculomotor apraxia type 2 (AOA2) and a form of juvenile amyotrophic lateral sclerosis, ALS4 (Chen et al., 2004; Moreira et al., 2004). SETX is an RNA/DNA helicase that functions in multiple events related to RNA metabolism and DNA maintenance, including transcriptional termination at certain genes and the DNA damage response at replication stress foci. A key role attributed to SETX in both of these functions is in the resolution of R loops, potentially deleterious DNA:RNA hybrid structures that form during transcription (Aguilera and Garcia-Muse, 2012). As abnormal levels of R loops are frequently observed in neurological disorders, this role has been proposed as a link between SETX dysfunction and neurodegeneration (Richard and Manley, 2016). In a recently published study, however, we demonstrated that SETX plays critical roles in the progression of autophagy, the process employed by cells to eliminate defective proteins and organelles, through its effects on expression of autophagy-related genes (Richard et al., 2020). A hallmark of neurodegenerative disease is the abnormal accumulation of protein aggregates that eventually lead to cellular dysfunction and degeneration of neuronal tissues (Kurtishi et al., 2019). Not surprisingly, defective autophagy is strongly implicated in the development of such disorders (Finkbeiner, 2020). As described in this perspective, we now suggest that this novel role for SETX provides an additional pathway by which transcriptional and gene expression defects caused by mutations in SETX can lead to neurological disease. Indeed, in preliminary analyses, we have detected perturbed autophagy in samples from AOA2 and ALS4 patients harboring SETX mutations.