First Mouse Model of AADC Deficiency Developed, Researchers Report

A mouse model of aromatic l-amino acid decarboxylase (AADC) deficiency, carrying a frequent mutation in patients with the condition, has been developed for the first time, according to researchers.

Findings from this new model indicate that low levels of the neurotransmitter serotonin are associated with characteristic symptoms.

The study, “A pathogenic S250F missense mutation results in a mouse model of mild aromatic l-amino acid decarboxylase (AADC) deficiency,” appeared in the journal Human Molecular Genetics.

AADC is the enzyme responsible for the final step in the production of dopamine and serotonin. Given the broad role of these neurotransmitters — which spans the control of voluntary movement, behavior, reward-based learning, gastrointestinal function, the respiratory and cardiovascular systems, and pain — AADC deficiency leads to various symptoms that start in infancy.

Since the original report of AADC deficiency in 1990, 28 missense AADC gene mutations — changes that lead to a different amino acid in the protein sequence — have been associated with this disorder, although with varying degrees of disease severity.

Prior attempts to develop a mouse model have failed because they either did not mimic the precise genetic alteration of patients or they resulted in embryonic death.

Aiming to address this, a research team from the Columbia University Medical Center, created a mouse model of AADC deficiency that carries a homozygous mutation (in both gene copies), known as S250F, meaning replacement of the amino acid serine by phenylalanine. This mutation had been linked to milder disease severity and is the second most commonly reported gene alteration in these patients (nearly 10% of cases), according to the researchers.

The mice showed very low AADC activity (less than 4% of the original protein), although the protein was stable and its levels were normal. Dopamine levels in the brain’s basal ganglia — primarily implicated in motor control — were only modestly changed, and neurons in the substantia nigra — part of the basal ganglia and critical in Parkinson’s disease — remained intact, suggesting no degeneration.

“We conclude that even minimal amounts of active AADC are sufficient to produce significant concentrations of dopamine and that low amounts of the enzyme per se do not impact the dopaminergic system,” the researchers wrote.

In contrast, serotonin levels were significantly reduced by more than 60%. Although the mice had a normal life expectancy, this decrease impaired behavior and autonomic function, reflected by weight gain in adult mice, impaired ability to maintain body temperature, motor deficits, and poor maternal instinct.

These mice are “the first example of a rodent mutant that harbors an identified human AADC deficiency mutation and, moreover, exhibits a disease phenotype,” the scientists wrote, adding that this model “is expected to serve as a useful tool in the pre-clinical development of effective therapies for human AADC deficiency.”