In this study, we report novel findings that autophagy is triggered through MCOLN1-calcineurin-dependent TFEB activation in 6-OHDA/AA-lesioned models of PD, and that further promotion of autophagy through TFEB enhancers can greatly rescue SH-SY5Y cells, iPSC-derived and mouse SNc-dopaminergic neurons from 6-OHDA/AA induced neurotoxicity. Here, MCOLN1 is linked to Parkinson disease.