How　complex　interactions　of　genetic,　environmental　factors　and　aging　jointly　contribute　to　dopaminergic　degeneration　in　Parkinson＇s　disease　(PD)　is　largely　unclear.　Here,　we　applied　frequent　gene　co-expression　analysis　on　human　patient　substantia　nigra-specific　microarray　datasets　to　identify　potential　novel　disease-related　genes.　In　vivo　Drosophila　studies　validated　two　of　32　candidate　genes,　a　chromatin-remodeling　factor　SMARCA4　and　a　biliverdin　reductase　BLVRA.　Inhibition　of　SMARCA4　was　able　to　prevent　aging-dependent　dopaminergic　degeneration　not　only　caused　by　overexpression　of　BLVRA　but　also　in　four　most　common　Drosophila　PD　models.　Furthermore,　down-regulation　of　SMARCA4　specifically　in　the　dopaminergic　neurons　prevented　shortening　of　life　span　caused　by　α-synuclein　and　LRRK2.　Mechanistically,　aberrant　SMARCA4　and　BLVRA　converged　on　elevated　ERK-ETS　activity,　attenuation　of　which　by　either　genetic　or　pharmacological　manipulation　effectively　suppressed　dopaminergic　degeneration　in　Drosophila　in　vivo.　Down-regulation　of　SMARCA4　or　drug　inhibition　of　MEK/ERK　also　mitigated　mitochondrial　defects　in　PINK1　(a　PD-associated　gene)-deficient　human　cells.　Our　findings　underscore　the　important　role　of　epigenetic　regulators　and　implicate　a　common　signaling　axis　for　therapeutic　intervention　in　normal　aging　and　a　broad　range　of　age-related　disorders　including　PD.　©　2020　The　Authors.　Aging　Cell　published　by　Anatomical　Society　and　John　Wiley　&　Sons　Ltd