Video: Flying ability is being tested by adding 5 flies in a cylinder and tapping the cylinder gently on the table. Flies that are capable of flying will fly upon tapping, while those that cannot, will fall or attach to the wall of the cylinder. The left video shows the flight assay of pink1 mutant flies. None of the flies is capable of flying and are falling on the table or attaching to the wall upon tapping. The right video shows control flies that upon tapping fly.
The use of Drosophilamelanogaster in research gained popularity after the elucidation of the basic mechanism of heredity by Dr. Thomas Hunt Morgan in 1915, for which he was awarded the Nobel Prize. His findings are the basis for current genetics and Drosophila was initially used in developmental research. However, with the identification of genes that are causative of diseases, Drosophila has increasingly been used as animal model to study mechanisms underlying human diseases. Although the Drosophila genome consists of only four chromosomes, around 75% of genes identified to be disease-causing in humans have an orthologue in flies. When there is no fly orthologue of a human disease-causing gene, Drosophila models can still contribute to elucidating the disease pathways. An example for this is the human SNCA gene, which can harbor causative PD mutations. The Drosophila genome does not carry an orthologue for SNCA, however, ectopic expression of human SNCA results in loss of dopaminergic neurons and locomotion defects, corresponding to symptoms observed in PD patients. Furthermore, the use of Drosophila in the laboratory has many advantages, including low cost, a short generation time, a high number of progeny, wide variety of genetic tools, and comparatively simple possibilities of genetic manipulation. Specific mutations can be introduced to mimic the disease-causing genotype, but also overexpression, knockdown or loss-of-function alleles can be created to study the function of disease-related proteins. One of the major tools that allow the identification of certain alleles in the fly genome is the use of marker chromosomes. These often comprise a combination of several phenotypic markers that are visible using a regular stereomicroscope, such as shape or color of the eye and shape of the wings.
The Drosophila laboratory has already established several neurodegenerative disease fly models, including models for PD and fatty acid hydroxylase-associated neurodegeneration. Furthermore, there is easy access to additional Drosophila models via stock centers (e.g. Bloomington Stock Center, Vienna Drosophila Resource Center) that collect most of the published new flies stocks (overexpression, knockdown, loss-of-function alleles) or via scientific collaborations with other international Drosophila research laboratories.
With respect to reduced penetrance, several findings in homozygous as well as heterozygous PINK1 mutant carriers suggest the existence of this phenomenon in the context of genetic PD. Specifically, 10% of the pink1 mutant flies remain capable of flying, implicating a mechanism of reduced penetrance. In a recent pilot study, we separated pink1 mutant flies originating from different parent pairs with a range of flying abilities from a complete lack to 40% of flying ability. This spectrum of phenotypes is paralleled by ATP levels, suggesting the presence of genetic modifiers that result in reduced penetrance of the phenotypes in Pink1-deficient flies.
Vos M, Esposito G, Edirisinghe JN, Vilain S, Haddad DM, Slabbaert JR, Van Meensel S, Schaap O, De Strooper B, Meganathan R, Morais VA, Verstreken P. Vitamin K2 is a mitochondrial electron carrier that rescues pink1 deficiency. Science 2012;336:1306-10.
Vos M, Lovisa B, Geens A, Morais VA, Wagnières G, Van den Bergh H, Gingen A, De Strooper B, Tardy Y, Verstreken P. Near-infrared light at 808 nm boosts Complex IV-dependent respiration and rescues a Parkinson-related pink1 model. Plos One 2013;8 e78562.
Morais VA, Haddad D, Craessaerts K, De Bock P-J, Swerts J, Vilain S, Aerts L, Overbergh L, Grünewald A, Seibler P, Klein C, Gevaert K, Verstreken P, De Strooper B. PINK1 loss of function mutations affect Complex I activity via NdufA10 ubiquinone uncoupling. Science 2014;344:203-207.