Psychomotor impairments and therapeutic implications revealed by a mutation linked with Infantile Parkinsonism-Dystonia

Parkinson's disease (PD) is a neurodegenerative disorder affecting over 6.1 million people worldwide. Studies of highly-penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the mechanisms underlying PD. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a type of infantile parkinsonism-dystonia that shares clinical features with PD. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. This R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. The disruption of this IC network supported a channel-like intermediate of hDAT and compromised hDAT function. Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, DA dysfunction in isolated brains and abnormal motor behaviors monitored at high-speed time resolution. These behaviors are linked with altered dopaminergic signaling, loss of DA neurons and decreased DA availability.