Neurodegenerative models in Drosophila: polyglutamine disorders, Parkinson disease, and amyotrophic lateral sclerosis

Abstract

Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue.

Fig. 1

Retinal phenotypes (or lack thereof) or various human neurodegenerative disease genes (tangential views). A and B, toludine blue-stained plastic sections. A, control retina shows normal ommatidia with regular profiles of seven rhabdomeres. B, huntingtin GMR-Q120 (GMR-Q120/+)(Jackson et al., 1998) fly at ten days shows degeneration of photoreceptor cells. C, the “pure” polyglutamine construct under control of GMR-GAL4 (GMR-GAL4/UAS-Q108)(Marsh et al., 2000) shows severely abnormal rhadomeres. Red, TRITC-phalloidin; green, htt17 (Sang et al., 2005); blue, lamin. D, the truncated MJD protein Q78 (GMR-GAL4/UAS-MJD-Q78) (Warrick et al., 1998) shows degenerated rhadomeres with largely nuclear localization of HA tagged aggregates. Red, TRITC-phalloidin; green, ant-HA; blue, lamin. E, The huntingtin exon 1 Q93 phenotype (Steffan et al., 2001) shows severe rhabdomere abnormaities (GMR-GAL4/UAS-htt-Q93). Red, phalloidoin TRITC; blue, TUNEL staining. F, the tau eye phenotype (GMR or gl-Tau/+) (Jackson et al., 2002)(see accompanying article by Wentzell and Kretzschmar for further discussion) shows abnormal polarity and some loss of rhabodmeres, with both diffuse and aggregated patterns of tau staining. Blue, phalloidoin-Cy3; red, total tau (T14); blue Alz50 (a conformation dependent tau epitope). G and H, phalloidoin-TRITC. G, control GMR-GAL4 retina (GMR-GAL4/+) at 60 days shows some mild irregularities and rhadomere droupout. The familial PD gene T240R, which shows dominant toxicity to DA neurons (Sang et al., 2007), has no obvious effect in retina greater than that of driver alone even at 60 days (GMR-GAL4/UAS-parkin^T240R). Thus, contrary to popular belief, it is not trivial to obtain retinal phenotypes in the fly by misexpressing human genes. Adapted from (Jackson et al., 1998; Jackson et al., 2002; Sang et al., 2007; Sang and Jackson, 2005; Sang et al., 2005).

Fig. 2

Indirect flight muscle degeneration in dparkin mutants. Confocal images of phalloidin-stained muscle preps. A, control muscle shows normal organization of sarcomeres. Arrowheads, normal Z bands. B, parkin null mutant shows irregularly sized and spaced sarcomere. Adapted from (Sang et al., 2007).