Mutations in the dopamine transporter (DAT) gene cause hereditary dopamine transporter deficiency syndrome (DTDS), a rare condition often involving defective transporter trafficking and folding. Screening known DAT ligands revealed that bupropion and ibogaine increase DAT surface expression, while cocaine and methylphenidate do not. These drugs raise wild-type DAT protein levels and promote maturation of the ER-retained mutant K590A, an effect blocked by inhibiting ER-to-Golgi transport or by knocking down the COPII component SEC24D. Both drugs also rescue maturation and functional activity of DTDS-associated mutations A314V and R445C. This is the first demonstration of pharmacological chaperoning of DAT, suggesting a potential therapeutic approach for DTDS and related conditions.
Mutations in the dopamine transporter gene cause Dopamine Transporter Deficiency Syndrome (DTDS), a fatal infantile parkinsonism-dystonia with no current treatment. Pharmacological chaperones can rescue some disease-causing variants. This study examined structure-activity relationships for two known chaperones, bupropion and ibogaine. The isoquinuclidine substituent of ibogaine and its analogs is important for chaperone efficacy. For bupropion, the secondary amine group is essential. Additional analogs with varying chemical modifications showed variable chaperone efficacies, contributing to the design of improved dopamine transporter pharmacological chaperones.