DNAJC12 in dopamine biology, physiology and related-behavior

Dopamine signaling in the brain is essential for movement, cognition, motivation and reward. Conversely, dopamine dysregulation has long been implicated in parkinsonism, dystonia and neuropsychiatric disorders. Recently, our laboratory discovered loss-of-function mutations in a protein chaperone, DNAJC12, as a cause of young-onset parkinsonism. Our findings coincided with another report of similar mutations in infants with dystonia, hyperphenylalanemia and intellectual disability. Now frequently identified through newborn screening, biallelic DNAJC12 mutations in infants and adults lead to a reduction in brain dopamine that is responsible for their movement disorders. However, the fundamental roles of DNAJC12 protein in catecholamine production are poorly described. To fill this knowledge gap, we have characterized a genetic mouse model in which Dnajc12 has been constitutively ablated and showed that at three months of age, these mice have reduced locomotion/exploratory behavior and reduced striatal dopamine, congruent with the function of Dnajc12. We now aim to specifically ablate Dnajc12 in dopaminergic neurons, which are prominently affected in Parkinson’s disease, to ascertain the effects of this gene dysfunction on dopamine synthesis, physiology and related behavior. Hence, our studies are to provide regulatory insights into dopamine biosynthesis from a unique biological perspective. The findings may reveal novel approaches to maintain or restore brain dopamine, which would have wide applicability.