Scientist: AADC deficiency can cause neurodegeneration in brain
Viewing AADC deficiency as neurodegenerative may open new treatment paths
Although AADC deficiency is characterized by low levels of signaling molecules in the brain that impair its normal function, the disease may also cause neurodegeneration, a study suggests.
Understanding how the disease may result in the gradual dysfunction, and ultimately death, of brain nerve cells could open up new avenues for treating the disease, a scientist proposed in the study “Neurodegenerative Etiology of Aromatic L-Amino Acid Decarboxylase Deficiency: a Novel Concept for Expanding Treatment Strategies,” which was published in Molecular Neurobiology.
AADC deficiency is caused by mutations in the DDC gene, which provides instructions for making the AADC enzyme. This enzyme is needed to make certain neurotransmitters, including dopamine and serotonin. Neurotransmitters are signaling molecules that nerve cells use to communicate with each other and with the rest of the body.
Having deficient levels of the AADC enzyme means that nerve cells in the brain aren’t able to make enough dopamine and serotonin and send these neurotransmitter signals as normal.
Reduced brain signaling implicated in AADC deficiency symptoms
These disruptions in brain signaling are thought to be the main mechanism behind the neurologic symptoms of AADC deficiency, and treatments have generally aimed to increase dopamine and/or serotonin signaling.
However, in this recent study, Zohi Sternberg, PhD, a scientist at Buffalo Medical Center in New York, asserts that reduced brain signaling is only part of the story.
Sternberg’s basic argument is that the lack of AADC enzyme doesn’t only prevent dopamine and serotonin production, but it also means intermediary molecules, which the enzyme normally uses to make these neurotransmitters, aren’t being used up like normal, and so build up to excessive levels.
In the paper, Sternberg gave a detailed overview of how AADC deficiency leads to a buildup of intermediary molecules such as 3-OMD and L-dopa, which are usually used to make dopamine. He then discussed how high levels of these molecules could have toxic effects on cells in the brain.
Specifically, elevated levels of 3-OMD and L-dopa have been shown to trigger inflammation in the brain, or neuroinflammation, which is thought to drive neurodegeneration in many brain disorders. These molecules also may cause abnormal nerve cell activity that can be toxic.
Sternberg also covered how these intermediary molecules can trigger a type of cellular damage called oxidative stress. In nerve cells, this can then trigger the activation of microglia, the brain’s resident innate immune cells, which in turn can promote neuroinflammation.
Oxidative stress can also be harmful to mitochondria, which provide energy to cells. Nerve cells normally require a lot of energy to send electrical signals, so they are especially sensitive to mitochondrial damage.
Overall, the reviewed evidence suggests oxidative stress in AADC deficiency may work “as an ignition for the downstream pathophysiological [disease-driving] processes culminating to mitochondrial dysfunction, neuroinflammation, and neuronal injury and death,” Sternberg wrote.
These mechanisms closely resemble what happens in other neurodegenerative diseases such as Parkinson’s, which is characterized by the progressive loss of dopamine-producing cells that ultimately leads to low levels of AADC.
“We believe that the [variability] in the clinical outcomes of established treatments … [in AADC deficiency] may be related in part to the progression of the disease where the chronic presence of several upregulated metabolites leads to irreversible damage of neurons, compromising their functional integrity,” Sternberg added.
As such, understanding AADC deficiency as a neurodegenerative disease, not just as the result of brain signaling disruption, may have major implications for how the disease is treated.
Treatment possibilities include COMT inhibitors, erythropoietin, antioxidants
“The new concept of [AADC deficiency] as a neurodegenerative disease opens a path for additional treatment modalities to reduce the levels of the upregulated metabolites, and or minimize the downstream pathophysiological processes,” Sternberg wrote. “This in turn would generate a more hospitable environment, where the clinical efficacy of [AADC deficiency] treatments, aimed at restoring neurotransmitters’ synthesis and or function, would be enhanced.”
These additional approaches may include drugs called COMT inhibitors, which are able to reduce levels of the dopamine metabolite 3-OMD. If excessive 3-OMD levels drive neurodegeneration in AADC deficiency, these medications could help to protect nerve cells against damage.
Another molecule called erythropoietin has been shown to reduce oxidative stress triggered by excess L-dopa levels in lab experiments, making it a potential therapeutic candidate in this regard, Sternberg noted.
Using similar logic, the researcher argued that antioxidants — a broad term referring to any molecule that can reduce oxidative stress — could offer benefits in AADC deficiency. This could involve either taking antioxidants and/or therapies that prompt brain cells to make more of their own antioxidants.
“These treatment modalities used singly or in combination, early in the course of the disease, will minimize neuronal injury, preserving the functional integrity of neurons, hence improving the clinical outcomes of both conventional and unconventional interventions in [AADC deficiency],” Sternberg wrote.