Levodopa therapy could ease SMA symptoms, per new mouse study
Problems in how dopamine and other chemical messengers work in nerve cells can cause issues with posture in spinal muscular atrophy (SMA), according to a new study in mice that also suggests that levodopa therapy — which works by increasing the levels of dopamine — could help ease such symptoms.
“Dopamine and [other chemical messengers] strongly influence locomotion [movement], and their dysregulation initiates the development of motor impairments linked to neurodegenerative disease,” like SMA, the scientists wrote.
Their research found that “treatment with [levodopa] provides therapeutic benefit in posture and locomotion in SMA mice.”
More work will be needed to advance this research, but these preclinical findings suggest levodopa therapy as a potential treatment target, according to the team.
The study, “Catecholaminergic dysfunction drives postural and locomotor deficits in a mouse model of spinal muscular atrophy,” was published in the journal Cell Reports by a team of researchers in the U.S. and Europe.
Use of levodopa therapy tested in SMA mouse model
In SMA, muscle weakness due to the shortage of a protein called SMN can cause problems with posture, and maintaining posture is important for sitting and walking. Catecholamines, a class of chemical messengers that include dopamine and noradrenaline, also called norepinephrine, play a key role in controlling movement.
Sometimes, however, catecholamines fail to send messages as well as they should — which can trigger the development of motor impairments linked to SMA and other neurodegenerative diseases.
“However, the precise cellular and circuit mechanisms are not well defined,” the researchers wrote.
To learn more, a team from the U.S., Germany, and Greece used mice genetically modified in the gene coding for SMN to mimic SMA. These mice are smaller than their wild-type (normal) littermates at birth and show progressive muscle weakness, similar to patients with the disease.
From early in the disease course, motor neurons gradually lost their catecholaminergic synapses — the points at which catecholamines like dopamine and noradrenaline are released to convey messages to other cells — the researchers found. Motor neurons are the nerve cells responsible for controlling movement in the body.
“There is an early and progressive loss of catecholaminergic synapses from vulnerable but not resistant motor neurons in SMA mouse models,” the researchers wrote. The team observed that synapses releasing dopamine were decreased by about half, whereas those releasing noradrenaline were reduced by about 35%.
Our study provides evidence that [levodopa] treatment should be considered to be an effective therapeutic avenue for SMA patients.
Four dopamine receptors — Drd2, Drd3, Drd4, Drd5 — were present in motor neurons, the team found. However, SMA mice had significantly fewer motor neurons producing Drd2 compared with wild-type mice. Other receptors remained unchanged, suggesting that the loss of dopaminergic synapses may cause changes in Drd2, according to the researchers.
In the SMA mice used in the study, the gene coding for the SMN protein can be reactivated with an enzyme called Cre. To study the effects of restoring SMN in dopamine-producing motor neurons, the SMA mice were bred with the animals producing Cre specifically in dopamine-producing motor neurons.
Reactivating that gene increased the number of catecholaminergic synapses on motor neurons. That showed that their loss was due to a shortage of the SMN protein, according to the team.
Similar observations were made when SMA mice were treated with levodopa, a widely used Parkinson’s medication that works by increasing the levels of dopamine, and benserazide, which prevents levodopa from being broken down, making more of it available.
Restoring SMN in either catecholamine- or serotonin-producing motor neurons was enough to ease difficulty moving and improve locomotion in SMA mice, the data showed. However, only levodopa or restoring SMN in both types of motor neurons improved posture. Serotonin, another chemical messenger, also plays a role in motor coordination in SMA.
“Our study provides evidence that [levodopa] treatment should be considered to be an effective therapeutic avenue for SMA patients,” the researchers wrote, noting their observations that dopamine and noradrenaline “may play a significant and more dominant role than motor neurons” themselves on motor symptoms.
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