Discovery of a gene whose overexpression prevents development of Parkinson's in fruit flies and mice

Discovery of a gene whose overexpression prevents development of Parkinson's in fruit flies and mice
Fer2 overexpression prevents the loss of PAM dopaminergic neurons and mitochondrial dysfunction in genetic models of PD. a, b Fer2 overexpression prevented the loss of PAM neurons induced by targeted expression of wild-type (WT) or pathogenic mutant Lrrk in PAM neurons. a Representative images of PAM neurons at day 14 detected by anti-TH antibodies (green). PAM, PAM neuron-specific R58E02-GAL4 driver. PAM > X indicates that UAS-transgene X is driven by R58E02-GAL4. Scale bar, 20 μm. Top left, a schematic of DA neurons in the PAM (green) and other clusters (black). b Quantification of the number of TH+ PAM neurons per hemisphere from (a). n = 16 hemispheres per group. **p < 0.01, ***p < 0.001, ****p < 0.0001. PAM vs. PAM > Lrrk WT, 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: Nature Communications (2022). DOI: 10.1038/s41467-022-29075-0

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 , 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 . 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 , 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 , their cells undergo 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 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

To find out whether Fer2 plays the same role in mammals, the biologists created mutants of the Fer2 homolog in mouse dopaminergic neurons. As in the fly, they observed abnormalities in the mitochondria of these neurons as well as defects in locomotion in aged mice. "We are currently testing the protective role of the Fer2 homolog in mice and results similar to those observed in flies would allow us to consider a new therapeutic target for Parkinson's disease patients," concludes Nagoshi.


Explore further

Fly protein has protective effect on dopaminergic neurons

More information: Federico Miozzo et al, Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor, Nature Communications (2022). DOI: 10.1038/s41467-022-29075-0
Journal information: Nature Communications

Citation: Discovery of a gene whose overexpression prevents development of Parkinson's in fruit flies and mice (2022, March 17) retrieved 7 August 2022 from https://medicalxpress.com/news/2022-03-discovery-gene-overexpression-parkinson-fruit.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.
34 shares

Feedback to editors