Background: Inherited mutations in the LRRK2 protein are common causes of Parkinson's disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10.
View Article and Find Full Text PDFLRRK2 mutations cause Parkinson's, but the molecular link from increased kinase activity to pathological neurodegeneration remains undetermined. Previous assays indicate that LRRK2 substrates include at least 8 Rab GTPases. We have now examined this hypothesis in a functional, electroretinogram screen, expressing each with/without in selected dopaminergic neurons.
View Article and Find Full Text PDFThere is increasing evidence for a strong genetic basis for autism, with many genetic models being developed in an attempt to replicate autistic symptoms in animals. However, current animal behaviour paradigms rarely match the social and cognitive behaviours exhibited by autistic individuals. Here, we instead assay another functional domain-sensory processing-known to be affected in autism to test a novel genetic autism model in Drosophila melanogaster.
View Article and Find Full Text PDFIn a number of models of genetic Parkinson's disease (PD) flies climb more slowly than wild-type controls. However, this assay does not distinguish effects of PD-related genes on gravity sensation, "arousal", central pattern generation of leg movements, or muscle. To address this problem, we have developed an assay for the fly proboscis extension response (PER).
View Article and Find Full Text PDFAn organism's biological day is characterized by a pattern of anticipatory physiological and behavioral changes that are governed by circadian clocks to align with the 24-h cycling environment. Here, we used flash electroretinograms (ERGs) and steady-state visually evoked potentials (SSVEPs) to examine how visual responsiveness in wild-type Drosophila melanogaster and the circadian clock mutant Clk varies over circadian time. We show that the ERG parameters of wild-type flies vary over the circadian day, with a higher luminance response during the subjective night.
View Article and Find Full Text PDFThe excitotoxic theory of Parkinson's disease (PD) hypothesizes that a pathophysiological degeneration of dopaminergic neurons stems from neural hyperactivity at early stages of disease, leading to mitochondrial stress and cell death. Recent research has harnessed the visual system of Drosophila PD models to probe this hypothesis. Here, we investigate whether abnormal visual sensitivity and excitotoxicity occur in early-onset PD (EOPD) Drosophila models DJ-1α, DJ-1β, and PINK1.
View Article and Find Full Text PDFMyoglianin, the Drosophila homolog of the secreted vertebrate proteins Myostatin and GDF-11, is an important regulator of neuronal modeling, and synapse function and morphology. While Myoglianin suppression during development elicits positive effects on the neuromuscular system, genetic manipulations of myoglianin expression levels have a varied effect on the outcome of performance tests in aging flies. Specifically, Myoglianin preserves jumping ability, has no effect on negative geotaxis, and negatively regulates flight performance in aging flies.
View Article and Find Full Text PDFSaposin deficiency is a childhood neurodegenerative lysosomal storage disorder (LSD) that can cause premature death within three months of life. Saposins are activator proteins that promote the function of lysosomal hydrolases that mediate the degradation of sphingolipids. There are four saposin proteins in humans, which are encoded by the prosaposin gene.
View Article and Find Full Text PDFElectrophysiological studies indicate altered contrast processing in some Parkinson's Disease (PD) patients. We recently demonstrated that vision is altered in Drosophila PD models and hypothesised that different types of genetic and idiopathic PD may affect dopaminergic visual signalling pathways differently. Here we asked whether visual responses in Drosophila could be used to identify PD mutations.
View Article and Find Full Text PDFThis study describes how the application of evolutionary algorithms (EAs) can be used to study motor function in humans with Parkinson's disease (PD) and in animal models of PD. Human data is obtained using commercially available sensors via a range of non-invasive procedures that follow conventional clinical practice. EAs can then be used to classify human data for a range of uses, including diagnosis and disease monitoring.
View Article and Find Full Text PDFWe provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson's disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest.
View Article and Find Full Text PDFClass IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes.
View Article and Find Full Text PDFOur understanding of Parkinson's disease (PD) has been revolutionized by the discovery of disease-causing genetic mutations. The most common of these is the G2019S mutation in the LRRK2 kinase gene, which leads to increased kinase activity. However, the link between increased kinase activity and PD is unclear.
View Article and Find Full Text PDFFlies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstrates nonautonomous degeneration, and a spread of pathology. This provides a model consistent with Braak's hypothesis on progressive PD.
View Article and Find Full Text PDFParkinson's disease (PD) is associated with loss of dopaminergic signalling, and affects not just movement, but also vision. As both mammalian and fly visual systems contain dopaminergic neurons, we investigated the effect of LRRK2 mutations (the most common cause of inherited PD) on Drosophila electroretinograms (ERGs). We reveal progressive loss of photoreceptor function in flies expressing LRRK2-G2019S in dopaminergic neurons.
View Article and Find Full Text PDFCytoplasmic accumulation and nuclear clearance of TDP-43 characterize familial and sporadic forms of amyotrophic lateral sclerosis and frontotemporal lobar degeneration, suggesting that either loss or gain of TDP-43 function, or both, cause disease formation. Here we have systematically compared loss- and gain-of-function of Drosophila TDP-43, TAR DNA Binding Protein Homolog (TBPH), in synaptic function and morphology, motor control, and age-related neuronal survival. Both loss and gain of TBPH severely affect development and result in premature lethality.
View Article and Find Full Text PDFParkinson's disease (PD) is characterized by movement disorders, including bradykinesia. Analysis of inherited, juvenile PD, identified several genes linked via a common pathway to mitochondrial dysfunction. In this study, we demonstrate that the larva of the Drosophila parkin mutant faithfully models the locomotory and metabolic defects of PD and is an excellent system for investigating their inter-relationship.
View Article and Find Full Text PDFWe describe our methods for analysing muscle function in a whole intact small insect, taking advantage of a simple flexible optical beam to produce an inexpensive transducer with wide application. We review our previous data measuring the response to a single action potential driven muscle twitch to explore jumping behaviour in Drosophila melanogaster. In the fruitfly, where the sophisticated and powerful genetic toolbox is being widely employed to investigate neuromuscular function, we further demonstrate the use of the apparatus to analyse in detail, within whole flies, neuronal and muscle mutations affecting activation of muscle contraction in the jump muscle.
View Article and Find Full Text PDFSex peptides transferred during mating from male to female fly profoundly influence the female's behavior and physiology, including an increase in the movement of eggs along the oviduct. In the male ejaculatory duct, the authors have identified peristaltic waves that travel distally with an average frequency of 0.6 Hz.
View Article and Find Full Text PDFWe have developed a novel apparatus, an ergometer, to simultaneously measure the horizontal and vertical components of the work done during takeoff by the fruitfly, Drosophila. We confirm the anatomical prediction that all the work comes from the middle (mesothoracic) legs. With all six legs on the ergometer platform, displacement is directed roughly 45 degrees forwards or backwards.
View Article and Find Full Text PDFHow do deficits in neuronal growth, aging or synaptic function affect the final, mechanical output of a single muscle twitch? We address this in vivo (indeed in situ) with a novel ergometer that records the output of a large specialised muscle, the Drosophila jump muscle. Here, we describe in detail the ergometer, its construction and use. We evaluated the ergometer by showing that adult fly jump muscle output varies little between 3 h and 7 days; but newly eclosed flies produce only 65%.
View Article and Find Full Text PDFParkinson's disease is a neurodegenerative disorder, related to the loss of dopamine (DA)-containing neurons in the substantia nigra. In experimental animals, both vertebrates and invertebrates, rotenone, a commercially available organic pesticide, induces symptoms of Parkinson's disease. We found that that rotenone is toxic to the pond snail Lymnaea stagnalis (4-day LC50 0.
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