Drosophila melanogaster as a model organism of brain diseases

Abstract

Drosophila melanogaster has been utilized to model human brain diseases. In most of these invertebrate transgenic models, some aspects of human disease are reproduced. Although investigation of rodent models has been of significant impact, invertebrate models offer a wide variety of experimental tools that can potentially address some of the outstanding questions underlying neurological disease. This review considers what has been gleaned from invertebrate models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, metabolic diseases such as Leigh disease, Niemann-Pick disease and ceroid lipofuscinoses, tumor syndromes such as neurofibromatosis and tuberous sclerosis, epilepsy as well as CNS injury. It is to be expected that genetic tools in Drosophila will reveal new pathways and interactions, which hopefully will result in molecular based therapy approaches.

Keywords: Fly; brain disease; drosophila.

Figure 1.

GAL4-UAS system: Transgenic flies expressing GAL4, a yeast transcriptional activator, are crossed against UAS-transgenic flies, carrying a gene of interest (“gene X”), inserted downstream of the UAS (upstream activating sequence;green balls). “Gene X” is activated in the offspring by crossing the two transgenic lines. The transgene is expressed in a time-/tissue dependent manner dependent on the selected GAL4-driver line.

Figure 2.

Forward genetic screen: Chemical mutagenesis (the chemical mutagen ethyl methane sulphonate (EMS) is common) or insertional mutagenesis techniques, having a disease-causing human gene, Enhancer-Promoter (EP)-element or RNAi construct placed under control of GAL4-responsive UAS sites are used to investigate the effect in specific tissues or the whole organism e.g. change of eye color (as indicated), reduced life-span, behavioral abnormalities or neuronal degeneration.

Figure 3.

Modifier screens: A modifier screen is conducted in order to find genes that play a role in a process of interest. Random mutations created by mutagenesis or selected mutants already suspected to be involved in the pathway investigated as well as collections of Enhancer-Promoter (EP)-elements and RNAi stocks may be used to identify genes able to modify (enhance or suppress) the phenotype. In this figure suppression and enhancement of an eye phenotype is illustrated.

Figure 4.

Drosophila embryonal CNS: a) Schematic view of the Drosophila CNS and ventral nerve cord with brain hemispheres (bh), midline glial cells and commissures. b) Ventral view of the ventral nerve cord: Commissures, midline glial cells as well as subperineurial, peripheral and channel glial cells. (pictures modified after V. Hartenstein.)

Figure 5.

Drosophila larval CNS:Schematic overview of a Drosophila larva showing brain (b), eye imaginal discs (ed), wing discs (wd), leg discs (ld), mouth hooks (mh) and gonads (gd).Magnification: Schematic view of brain hemispheres (b), eye imaginal discs (ed) as well as antennal discs (ad). The eye imaginal disc will form the adult compound eye whereas the antennal disc will develop into the antenna, the adult olfactory organ. The optic stalk (os) connects the brain hemispheres with the eye imaginal discs, whereas Bolwig nerve (Bn) constitutes the link of the larval brain to the larval photo receptors.

Figure 6.

Drosophila adult CNS and compound eye: a) Frontal view of the adult Drosophila brain. Highlighted are mushroom bodies and the central complex (yellow) as well as the optic lobes (green).b) Tangential section of a Drosophila compound eye reveals the highly stereotyped arrangement of ommatidia. Here the organization of photoreceptors for a single ommatidium is illustrated. Numbers 1–7 indicate the light-sensing organelles of the photoreceptors, called rhabdomeres. Photoreceptors R1-R6 have a longer rhabdomere and represent the outer photoreceptors, as they surround the inner rhabdomeres R7 and R8. In this section only R7 is visible as R8 sits directly underneath.