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Discovery of a gene whose overexpression prevents development of Parkinson's in fruit flies and micecan you use albuterol when pregnant p = 0.0026. PAM vs. PAM > Lrrk I1915T, p = 0.0002. PAM > Lrrk I1915T vs. PAM > Lrrk I1915T, Fer2, p = 0.0001. ns, not significant. One-way ANOVA followed by a Tukey’s test for multiple group comparison. c Representative images of PAM neurons at day 14 labeled by PAM > Red Stinger. Scale bar, 20 μm. d Quantification of the number of Red Stinger+ PAM neurons per hemisphere from (c). n = 16 hemispheres per group. ****p < 0.0001. ns, not significant. One-way ANOVA followed by a Tukey’s test for multiple group comparison. e The mitochondrial network in PAM neurons was visualized using mitoGFP. Scale bar, 5 μm. f Top, histograms showing the circularity distribution of GFP+ particles measured from (e). Bottom, the Gaussian curve fit to the circularity histogram. Circularity ranges from 0 (reticular mitochondria) to 1 (round mitochondria). ****p < 0.0001 using Kruskal–Wallis test followed by Dunn’s test for multiple group comparison. 500 mitochondrial particles were analyzed from 16 hemispheres per genotype. g Quantification of TMRM fluorescence intensity in GFP-labeled PAM neurons in 14-days-old flies. n = 18 hemispheres per group. HE, heterzogous. HO, homozygous. **p < 0.01. PAM > EGFP vs. Park1 HO, PAM > EGFP, p = 0.0063. Park1 HO, PAM > EGFP vs. Park1 HO, PAM > EGFP, Fer2, p = 0.0016. ns, not significant. One-way ANOVA followed by a Tukey’s test for multiple group comparison. Box boundaries in (b), (d) and (g) are the 25th and 75th percentiles, the horizontal line across the box is the median, and the whiskers indicate the minimum and maximum values. Credit: <i>Nature Communications</i> (2022). DOI: 10.1038/s41467-022-29075-0″ width=”800″ height=”530″>

Parkinson’s disease is a neurodegenerative disorder characterized by the destruction of a specific population of neurons: the dopaminergic neurons. The degeneration of these neurons prevents the transmission of signals controlling specific muscle movements and leads to tremors, involuntary muscle contractions or balance problems characteristic of this pathology. A team from the University of Geneva (UNIGE) has investigated the destruction of these dopaminergic neurons using the fruit fly as study model. The scientists identified a key protein in flies, and also in mice, which plays a protective role against this disease and could be a new therapeutic target. This work can be read in the journal Nature Communications.

Apart from rare forms involving a single gene, most Parkinson’s cases result from an interaction between multiple genetic and environmental risk factors. However, a common element in the onset of the disease is a dysfunction of mitochondria in dopaminergic neurons. These small factories within cells are responsible for energy production, but also for activating the cell’s self-destruct mechanisms when damaged.

The laboratory of Emi Nagoshi, Professor in the Department of Genetics and Evolution at the UNIGE Faculty of Science, uses the fruit fly, or Drosophila, to study the mechanisms of dopaminergic neuron degeneration. Her group is particularly interested in the Fer2 gene, whose human homolog encodes a protein that controls the expression of many other genes and whose mutation might lead to Parkinson’s disease via mechanisms that are not yet well understood.

In a previous study, this scientific team demonstrated that a mutation in the Fer2 gene causes Parkinson’s-like deficiencies in flies, including a delay in the initiation of movement. They had also observed defects in the shape of the mitochondria of dopaminergic neurons, similar to those observed in Parkinson’s patients.

Protecting neurons

Since the absence of Fer2 causes Parkinson’s disease-like conditions, the researchers tested whether—on the contrary—an increase in the amount of Fer2 in the cells could have a protective effect. When flies are exposed to free radicals, their cells undergo oxidative stress which leads to the degradation of dopaminergic neurons. However, the scientists were able to observe that oxidative stress no longer has any deleterious effect on the flies if they overproduce Fer2, confirming the hypothesis of its protective role.

“We have also identified the genes regulated by Fer2 and these are mainly involved in mitochondrial functions. This key protein therefore 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,” explains Federico Miozzo, researcher in the Department of Genetics and Evolution and first author of the study.

A new therapeutic target

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