Circadian Rhythm Abnormalities in Parkinson's Disease from Humans to Flies and Back

Clinical and research studies have suggested a link between Parkinson\u2019s disease (PD) and alterations in the circadian clock. Drosophila melanogaster may represent a useful model to study the relationship between the circadian clock and PD. Apart from the conservation of many genes, cellular mechanisms, signaling pathways, and neuronal processes, Drosophila shows an organized central nervous system and well-characterized complex behavioral phenotypes. In fact, Drosophila has been successfully used in the dissection of the circadian system and as a model for neurodegenerative disorders, including PD. Here, we describe the fly circadian and dopaminergic systems and report recent studies which indicate the presence of circadian abnormalities in some fly PD genetic models. We discuss the use of Drosophila to investigate whether, in adults, the disruption of the circadian system might be causative of brain neurodegeneration. We also consider approaches using Drosophila, which might provide new information on the link between PD and the circadian clock. As a corollary, since PD develops its symptomatology over a large part of the organism\u2019s lifespan and given the relatively short lifespan of fruit flies, we suggest that genetic models of PD could be used to perform lifelong screens for drug-modulators of general and/or circadian-related PD traits

Arg206 of SNAP-25 is essential for neuroexocytosis at the Drosophila melanogaster neuromuscular junction

An analysis of SNAP-25 isoform sequences indicates that there is a highly conserved arginine residue (198 in vertebrates, 206 in the genus Drosophila ) within the C-terminal region, which is cleaved by botulinum neurotoxin A, with consequent blockade of neuroexocytosis. The possibility that it may play an important role in the function of the neuroexocytosis machinery was tested at neuromuscular junctions of Drosophila melanogaster larvae expressing SNAP-25 in which Arg206 had been replaced by alanine. Electrophysiological recordings of spontaneous and evoked neurotransmitter release under different conditions as well as testing for the assembly of the SNARE complex indicate that this residue, which is at the P 1 ′ position of the botulinum neurotoxin A cleavage site, plays an essential role in neuroexocytosis. Computer graphic modelling suggests that this arginine residue mediates protein–protein contacts within a rosette of SNARE complexes that assembles to mediate the fusion of synaptic vesicles with the presynaptic plasma membrane

The clock gene period in the medfly Ceratitis capitata.

We have isolated the clock gene period (per) from the medfly Ceratitis capitata, one of the most economically important insect pest species. The overall pattern of conserved, non-conserved and functional domains that are observed within dipteran and lepidopteran per orthologues is preserved within the coding sequence. Expression analysis from fly heads revealed a daily oscillation in per mRNA in both light[ratio ]dark cycles and in constant darkness. However PER protein levels from head extracts did not show any significant evidence for cycling in either of these two conditions. When the Ceratitis per transgene under the control of the Drosophila per promoter and 3′UTR was introduced into Drosophila per-null mutant hosts, the transformants revealed a low level of rescue of behavioural rhythmicity. Nevertheless, the behaviour of the rhythmic transformants showed some similarities to that of Ceratitis, suggesting that Ceratitis per carries species-specific information that can evidently affect the Drosophila host's downstream rhythmic behaviour

UCP4C mediates uncoupled respiration in larvae of Drosophila melanogaster

Larvae of Drosophila melanogaster reared at 23\ub0C and switched to 14\ub0C for 1 h are 0.5\ub0C warmer than the surrounding medium. In keeping with dissipation of energy, respiration of Drosophila melanogaster larvae cannot be decreased by the F-ATPase inhibitor oligomycin or stimulated by protonophore. Silencing of Ucp4C conferred sensitivity of respiration to oligomycin and uncoupler, and prevented larva-to-adult progression at 15\ub0C but not 23\ub0C. Uncoupled respiration of larval mitochondria required palmitate, was dependent on Ucp4C and was inhibited by guanosine diphosphate. UCP4C is required for development through the prepupal stages at low temperatures and may be an uncoupling protein

Phenotypic effects induced by knock-down of the period clock gene in Bombyx mori.

SummaryThe lepidopteranBombyx moriis an insect of considerable scientific and economic importance. Recently, theB. moricircadian clock geneperiodhas been molecularly characterized. We have transformed aB. moristrain with a construct encoding aperioddouble-strand RNA in order to knock-downperiodgene expression. We observe that this post-transcriptional silencing produces a small but detectable disruption in the egg-hatching rhythm, as well as a reduction in egg-to-adult developmental time, without altering silk production parameters. Thus we show that both circadian and non-circadian phenotypes can be altered by changingperexpression, and, at a practical level, these results suggest thatperknock-down may provide a suitable strategy for improving the efficiency of rearing, without affecting silk productivity

Circadian Clock Dysfunction and Psychiatric Disease: Could Fruit Flies have a Say?

There is evidence of a link between the circadian system and psychiatric diseases. Studies in humans and mammals suggest that environmental and/or genetic disruption of the circadian system leads to an increased liability to psychiatric disease. Disruption of clock genes and/or the clock network might be related to the etiology of these pathologies; also, some genes, known for their circadian clock functions, might be associated to mental illnesses through clock-independent pleiotropy. Here, we examine the features which we believe make Drosophila melanogaster a model apt to study the role of the circadian clock in psychiatric disease. Despite differences in the organization of the clock system, the molecular architecture of the Drosophila and mammalian circadian oscillators are comparable and many components are evolutionarily related. In addition, Drosophila has a rather complex nervous system, which shares much at the cell and neurobiological level with humans, i.e., a tripartite brain, the main neurotransmitter systems, and behavioral traits: circadian behavior, learning and memory, motivation, addiction, social behavior. There is evidence that the Drosophila brain shares some homologies with the vertebrate cerebellum, basal ganglia, and hypothalamus-pituitary-adrenal axis, the dysfunctions of which have been tied to mental illness.We discuss Drosophila in comparison to mammals with reference to the: organization of the brain and neurotransmitter systems; architecture of the circadian clock; clock-controlled behaviors.We sum up current knowledge on behavioral endophenotypes, which are amenable to modeling in flies, such as defects involving sleep, cognition, or social interactions, and discuss the relationship of the circadian system to these traits. Finally, we consider if Drosophila could be a valuable asset to understand the relationship between circadian clock malfunction and psychiatric disease

Sensorless Current Control of a Soft-Starter for Induction Motors

The direct-on-line starting of induction motors produces troublesome torque and current transients. Soft starters enable a reduction of the motor sizing and more reliable operation; among different soft-starting control strategies, the closed-loop current control seems the most effective. This work proposes a novel sensorless current limitation for a soft-starter, in which the currents are estimated using only measurements of the thyristor conducting angles

Extended-Range PMSM Sensorless Speed Drive Based on Stochastic Filtering

The paper describes the design of a high-performance sensorless Permanent Magnet Synchronous Motor (PMSM) drive, capable of starting at full torque even from standstill and able to deliver full torque in 1:12 speed range. Experimental setup, hardware circuitry and software implementation are described into details. Particular emphasis is given to the software control algorithms, that were specifically studied to enhance the overall system performance