Nerve fiber growth troubled with disease, may affect gene therapy
Dopaminergic neurons fewer, slower in reaching key brain area in mouse model
Low levels of the nerve signaling molecule dopamine, a feature of aromatic l-amino acid decarboxylase (AADC) deficiency, affect the growth at early stages of nerve fibers in a brain region important for movement, a mouse study reveals.
Early nerve fiber growth in AADC-deficient mice lacked the precise guidance seen in healthy mice, with fibers taking a longer route and reaching this brain region later, delaying subsequent processes to eventually disrupt communication between nerve cells.
These defects may limit the efficacy of treatments for AADC deficiency, including gene therapy, according to the researchers. They suggest that early use of dopamine supplements or those of similar medications may increase nerve fiber growth in the brain and improve patient outcomes.
The study, “Nigrostriatal tract defects in mice with aromatic l-amino acid decarboxylase deficiency,” was published in the Neurobiology of Disease.
Dopaminergic neurons sparse in striatum of disease mice vs. healthy mice
AADC deficiency is caused by mutations in the DDC gene, leading to a deficiency in the AADC enzyme. This disrupts the production of dopamine and serotonin, two chemical messengers nerve cells use to communicate with each other.
Low levels of dopamine and serotonin in AADC patients impair communication between the brain and the rest of the body, leading to disease symptoms marked by developmental delays starting at a young age, typically in early infancy.
Gene therapy is a promising approach to treat AADC deficiency, and is designed to introduce a healthy version of the DDC gene into nerve cells. This would allow the production of a fully functional AADC enzyme and restore dopamine and serotonin levels.
Upstaza (eladocagene exuparvovec) is one such gene therapy, developed by PTC Therapeutics, that’s been shown to provide lasting and meaningful improvements in motor and cognitive function for children with AADC deficiency. It’s approved for use in the Europe Union and the U.K., and under an approval review in the U.S.
Still, clinical data revealed that some patients may not respond fully to gene therapy if they have low pretreatment levels of homovanillic acid, a product of dopamine metabolism, in their cerebrospinal fluid (surrounds the brain and spinal cord). Dopamine-producing nerve cells, or dopaminergic neurons, derived from an AADC patient also showed defects in electrical properties and synapse maturation. Synapses are the cell-to-cell junctions where nerve cells communicate.
Researchers at National Taiwan University Hospital, who are working on a separate potential gene therapy for AADC deficiency, conducted a detailed examination of the disease’s impact on dopaminergic neurons in the brains of mice lacking the Ddc gene, equivalent to the human gene. These mice exhibited severe motor dysfunction, uncontrolled involuntary muscle movements (dyskinesia), and growth delays, similar to AADC patients.
They focused on the nigrostriatal pathway, whereby dopaminergic neurons in the substantia nigra, a region of the midbrain, extend nerve fibers (axons) into the forebrain region called the striatum. It’s one of the four major dopamine pathways in the brain and is critical for movement.
Examinations showed that AADC mice had fewer dopaminergic neurons in the striatum than healthy control mice at 14 days of age, and the dopaminergic axons of disease mice were more sparse and irregular.
At the same age, the number of dopaminergic neurons in the substantia nigra and the number of dopaminergic nerve bundles leaving the substantia nigra were both normal. However, in AADC mice these nerve bundles were smaller, looser, and more dispersed, and they took abnormal routes into the striatum, which spread over a broader area. Generally, the total volume of the nigrostriatal tract was higher in AADC mice, while the fraction of dopaminergic neurons was lower.
‘First evidence’ of dopamine’s role in brain pathway critical for movement
Single-cell genetic analysis of healthy mice over the first 14 days of age demonstrated that dopaminergic neurons formed synapses with striatal neurons in the first week after birth. In comparison, the growth of axons and synapse formation was delayed in AADC mice.
Lastly, a cell-to-cell analysis revealed poorer communication between two types of striatal neurons (D1 and D2) that receive input from dopaminergic neurons. Conversely, more communication was evident between substantia nigra dopaminergic neurons and dopaminergic neuron precursor cells, which also may indicate “a delay in the maturation of the nigrostriatal pathway,” the researchers noted.
“Mice with AADC deficiency presented an aberrant route of nigrostriatal nerve bundles and decreased striatal innervation [dopaminergic neurons] due to congenital dopamine deficiency,” the researchers concluded. “Delayed synapse formation and abnormal cell-cell communication were also indicated.”
This study “is the first evidence for the role of dopamine in the development of the nigrostriatal pathway,” the researchers added. “The presence of nigrostriatal tract structural defects may explain the lack of treatment response” in some gene therapy patients enrolled in a clinical trial in Taiwan, who “do not achieve the same motor function after gene therapy as other patients do.”
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