Alpha-methyl-para-tyrosine and amphetamine ameliorate hyperactivity in a novel mouse model of dopamine transporter deficiency syndrome.

The dopamine transporter is essential for dopamine homeostasis maintenance. Therefore, single amino acid changes in its gene can be sufficient to induce disease, such as dopamine transporter deficiency syndrome (DTDS). DTDS-associated variants may lead to DAT protein misfolding, retention in the endoplasmic reticulum, and reduced DAT surface expression. In turn, proper dopaminergic regulation is lost. Current treatments for DTDS are largely ineffective, necessitating better options. We developed a novel mouse model of DTDS harboring the A313V knock-in DAT variant, a proxy for the human A314V variant. The A313V mice are hyperactive, have decreased striatal tissue content of dopamine and increases in its metabolite HVA, and impaired dopamine uptake. FDA approved compounds alpha-methyl-para-tyrosine and amphetamine ameliorate the observed hyperactivity. Moreover, alpha-methyl-para-tyrosine may be a disease-modifying treatment by addressing the hyperdopaminergic tone underlying this hyperactivity. Noribogaine, a pharmacological chaperone for DAT, is unable to rescue DAT expression. These findings demonstrate that the A313V knock-in DAT variant mice recapitulate several defining phenotypes seen in patients with DTDS, and provide evidence for two novel treatments for the disease.