Gene That Protects Dopamine-making Neurons Identified in Study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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A gene called Fer2 in fruit flies is essential for maintaining the health of dopamine-producing nerve cells and does so by supporting the cells’ mitochondria, which provide them with energy, a study reports.

The human equivalent of this gene — a mammalian equivalent, called Nato3, was identified in mice — may be a target for treating Parkinson’s disease, which is caused by the death and dysfunction of dopamine-producing cells in the brain, its scientists suggested.

The study, “Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor,” was published in Nature Communications.

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Dopamine is a neurotransmitter, a chemical messenger that neurons (nerve cells) use to communicate with each other and with other parts of the body. The death and dysfunction of dopaminergic (dopamine-producing) neurons in certain regions of the brain is what gives rise to Parkinson’s symptoms.

The Fer2 gene is known to be important for the development and health of dopaminergic neurons. This gene provides instructions for making a transcription factor, which is a kind of protein that controls gene expression in cells — regulating the extent to which different genes are turned “on” or “off,” which has far-reaching consequences for the activity and health of the cell.

A team at the University of Geneva first tested the effects of over-expressing Fer2 in two fruit fly models of familial Parkinson’s associated with mutations in the genes LRRK2 or PARK. Results showed that increasing Fer2 levels prevented the loss of dopaminergic neurons in these flies.

Further experiments showed that increased Fer2 levels conferred resistance against oxidative stress — cellular damage caused by highly reactive oxygen-containing molecules — in the fruit fly models. Oxidative stress has been implicated in Parkinson’s and other neurological disorders.

“Taken together, these results provide evidence that Fer2 is a potent neuroprotective transcription factor for [fruit fly] dopaminergic neurons, counteracting various genetic and oxidative insults,” the researchers wrote.

To understand the mechanisms underlying these effects, the researchers conducted tests to identify the genes that are regulated by Fer2.

Results showed that most of the genes regulated by the Fer2 transcription factor are themselves genes important for regulating gene expression, or activity. This indicates that Fer2 acts as a “master regulator,” controlling the expression of genes that then go on to control the expression of even more genes to enact its effect.

Further analyses of these target genes, and their downstream targets, revealed that many of the genes that Fer2 regulates are important for maintaining the health of mitochondria. Sometimes called the “powerhouse of the cell,” mitochondria play a critical role in generating energy in cells.

Neurons, which require a lot of energy to send electrical signals, are particularly susceptible to mitochondrial defects, and mitochondrial dysfunctional has been implicated in Parkinson’s development and progression.

The Fer2 gene “seems to play a crucial role against the degeneration of dopaminergic neurons in flies by controlling not only the structure of mitochondria but also their functions,” Federico Miozzo, a researcher at the University of Geneva and a study co-author, said in a press release.

In people, mice, and other mammals, a gene called Nato3 is the functional equivalent of Fer2. Previous research has shown that, without this gene, mice will not develop dopaminergic neurons.

In mice, unlike with Fer2 in flies, the Nato3 gene also is active in dopaminergic throughout life, not just during development.

To understand the function of Nato3 in living animals, the researchers engineered mice to lack this gene conditionally, once their dopaminergic neurons had developed and matured. These mice performed similarly to control mice on motor tests up to about 13 months of age, and then the engineered mice showed marked motor defects.

“These results indicate that Nato3 ablation in [mature dopaminergic] neurons lead to motor abnormalities in aged mice, possibly caused by an age-dependent decline in” the function of these dopaminergic neurons, the researchers wrote.

Further investigation also showed marked abnormalities in the mitochondria of dopaminergic neurons in aging mice lacking Nato3 in these neurons.

“These results demonstrate that Nato3 is required for the maintenance of mitochondrial integrity in the [dopaminergic] neurons” during aging, the researchers wrote.

“In light of our findings that Fer2 confers neuroprotection in multiple fly [Parkinson’s] models, it is tempting to speculate that the overexpression or activation of Nato3 may protect [dopaminergic] neurons from genetic and environmental insults in mammals, with potential far-reaching implications for [Parkinson’s] treatment,” the team concluded.

The scientists noted a need for further research to validate these findings, and to identify targets of Nato3 regulation in mammals.