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

## TL;DR

Researchers created a mouse model for a dopamine transporter disorder and found that two FDA-approved drugs can reduce hyperactivity in these mice.

## Contribution

A novel mouse model of dopamine transporter deficiency syndrome was developed, and two FDA-approved drugs were identified as potential treatments.

## Key findings

- A313V knock-in mice show hyperactivity, reduced dopamine, and impaired dopamine uptake.
- Alpha-methyl-para-tyrosine and amphetamine reduce hyperactivity in A313V mice.
- Pifithrin-μ increases DAT levels in the midbrain of A313V mice.

## Abstract

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.

The dopamine transporter (DAT) is a key protein in dopamine neurotransmission and homeostasis. Variants in the gene that encodes for DAT can lead to disease, such as Dopamine Transporter Deficiency Syndrome (DTDS). Here, a novel mouse model of DTDS was generated and pharmacological treatment strategies were assessed.

The A313V DAT knock-in mouse is a model of the A314V DAT variant that causes DTDS in humans.A313V mice have decreased mature DAT in the striatum and midbrain and increased levels of midbrain immature/total DAT.A313V mice have decreased striatal dopamine and DOPAC tissue content, and increased HVA.A313V mice are hyperactive compared to WT mice, and this hyperactivity is ameliorated with AMPH and αMPT.Treatment with pifithrin-μ increases the levels of DAT in the midbrain of A313V mice.

The A313V DAT knock-in mouse is a model of the A314V DAT variant that causes DTDS in humans.

A313V mice have decreased mature DAT in the striatum and midbrain and increased levels of midbrain immature/total DAT.

A313V mice have decreased striatal dopamine and DOPAC tissue content, and increased HVA.

A313V mice are hyperactive compared to WT mice, and this hyperactivity is ameliorated with AMPH and αMPT.

Treatment with pifithrin-μ increases the levels of DAT in the midbrain of A313V mice.

The dopamine transporter (DAT) is a key protein in dopamine neurotransmission and homeostasis. Variants in the gene that encodes for DAT can lead to disease, such as Dopamine Transporter Deficiency Syndrome (DTDS). Here, a novel mouse model of DTDS was generated and pharmacological treatment strategies were assessed.