A protein called scarlet can protect nerve cells from the damaging effects of toxic alpha-synuclein aggregates that occur in Parkinson’s disease, according to results of research into a fruit fly model.
The study, “Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants,” was published in the Journal of Cell Science.
Fruit flies (Drosophila melanogaster) have proven to be useful models to study Parkinson’s disease. Similar to what happens in humans, progressive loss of dopamine-producing brain cells leads to defects in locomotor function and control.
Upon screening a collection of fruit flies that showed degeneration of dopaminergic nerve cells, the team found some with mutations affecting the scarlet gene.
A detailed evaluation showed no significant differences in the number of dopaminergic neurons in the mutant flies compared to wild-type controls on day three. But, by day 18, the mutant flies had evident neurodegenerative onset, and by day 21 they had significantly lower numbers of neurons.
“These results demonstrate that loss of scarlet function is sufficient to promote degeneration of dopaminergic neurons,” the researchers wrote.
Scarlet mutant flies also had a shorter lifespan, with a median survival of 27 days compared to about 40 days in control flies. And these animals also impaired locomotor activity, with substantially climbing ability by day 11 and that continued to show decline by day 18.
To further explore the gene’s role, researchers induced the production of a normal scarlet gene in dopaminergic nerve cells of flies that carried its mutated version.
Using this approach, they were able to prevent neurodegeneration and rescue the progressive climbing defects previously observed. However, the flies’ lifespan was not expanded, which suggests that “Scarlet’s role in longevity requires more than [its presence] in dopaminergic neurons,” the researchers wrote.
Additional analysis revealed that flies that lacked scarlet had higher levels of potentially damaging reactive oxygen elements, also known as ROS. In contrast, flies that had been genetically altered — given a healthy working version of the scarlet gene — had lower ROS levels in the brain.
“Because dopaminergic neurons are particularly vulnerable to oxidative stress,” these findings suggest that scarlet’s role in Parkinson’s could in part be to limiting oxidative stress, the researchers wrote.
Oxidative stress is an imbalance between the production of free radicals and the ability of cells to detoxify them. These free radicals, or ROS, are harmful to cells and associated with a number of diseases, including Parkinson’s.
Researchers also explored the role of the scarlet protein in flies that had been genetically engineered to carry the human alpha-synuclein protein in dopaminergic neurons.
In the presence of alpha-synuclein — either the normal version or two mutated forms linked to familial Parkinson’s disease — flies experienced significant loss of dopamine-producing cells. But scarlet was present, even together with alpha-synuclein, the loss of dopamine-producing cells was prevented.
“The experiment demonstrated that Scarlet was sufficient in preventing dopaminergic neuron loss, suggesting a neuroprotective function,” Patrick Cunningham, a PhD student at Lehigh University and study author, said in a Journal of Cell Science interview.
“We found that the fruit fly mutant scarlet [gene], commonly associated with a bright red eye color, showed progressive DA [dopaminergic] neuron loss that was accompanied by impaired movement coordination,” Cunningham added. “A mutation causes errors in the protein that is associated with a specific gene; in other words, the scarlet mutant has a dysfunctional Scarlet protein.”
When the protein was added to mutant flies, it’s presence “showed a neuroprotective function by preventing the loss of DA neurons and maintaining movement coordination.”
The presence of scarlet protein, indeed, helped to ease difficulties with motor function — as seen in the climbing problems — that were induced by all three forms of alpha-synuclein.
“The identification of a neuroprotective role for Scarlet should help in characterizing the selective vulnerability of dopaminergic neurons in Parkinson’s disease,” the researchers wrote.
“Thus, investigating mechanisms uncovered here should be helpful for uncovering potential therapeutic targets to prevent the loss of these neurons,” they concluded.
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