Page 244 - 53rd Annual Drosophila Research Conference

Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
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We established a dose regimens of Diferuloylmethane (Curcumin) to assess its effectiveness on Drosophila HD model. Our findings indicate that 3 and
10μM concentrations of curcumin significantly ameliorate HD pathogenesis including aggregation. Interestingly, 10μM concentration of curcumin prevented
progressive impairment of motor function in “humanized” fly model. This data suggests that curcumin may serve as a potential therapeutic agent for patients
in the treatment of neurodegenerative diseases like HD without any side effect.
407B
A Parkinson’s Disease Model for the Characterization of Long Term Effects of Early Exposure to Environmental Toxins. James W. Anderson, Arati
Inamdar, O'Neil Wright, Janis O'Donnell. Biological Sciences, University of Alabama, Tuscaloosa, AL.
The degeneration of dopaminergic neurons, the central pathological feature of Parkinson’s disease (PD), leads to characteristic movement disorders only
after approximately 75% of the neurons in the midbrain have been lost. It is likely that susceptibility to idiopathic PD is defined by genetic variation acting
in concert with environmental triggers that may have occurred decades prior to the onset of symptoms. This extreme lag in manifestation of PD presents a
barrier for the identification of environmental risk factors and biomarkers for early events that can predispose an individual to this incurable
neurodegenerative disease. We employed a Drosophila PD model based on exposure to the herbicide paraquat (PQ), which triggers dopaminergic
neurodegeneration and movement deficits, as a system for defining mechanisms by which early events lead to later disease. We investigated whether a single
exposure to PQ during the larval stage had long-term consequences that led to the development of PD-like features or that sensitized individuals to
secondary environmental challenges in adult life. We found that larvae, fed for 12 hours only on 1-10mM PQ, subsequently exhibited parkinsonian
symptoms in adulthood, including persisting mobility defects and low dopamine levels in the adult brain. We find evidence of dopaminergic
neurodegeneration, as suggested by the diminished dopamine pools. We show that treated larvae are more sensitive to secondary exposure to PQ as adults.
Additionally, PQ treatment of larvae induces chronic neuroinflammation that persists through metamorphosis and into adulthood. This chronic inflammatory
response exacerbates the PQ-induced degeneration of dopaminergic neurons. Our data support the hypothesis that early exposure to environmental toxins is
a risk factor for developing PD. Furthermore, we provide evidence that altering the inflammatory response early in this process can ameliorate later
parkinsonian symptoms. In addition, we provide evidence for biomarkers with long-term alterations, which may facilitate early diagnosis.
408C
Mutations that Destabilize Helix-3 Induce Aberrant Processing of the Prion Protein. Daniela Arbelaez1,2, Jonatan Sanchez2, Pedro Fernandez-Funez 2,
Diego Rincon-Limas2 . 1) College of Liberal Arts and Sciences; 2) Department of Neurology, University of Florida, Gainesville, FL.
Prion diseases are caused by the misfolding of the normal prion protein (PrPc), a glycolipid-anchored membrane protein, into a toxic conformation (PrPsc).
The globular domain of PrP is stabilized by different intramolecular interactions, one being hydrophobic interactions between helix 1 and 3. In vitro studies
have shown that this well conserved hydrophobic core of PrP is stabilized by two Methionines (M205 and M212) in the helix 3 and that introduction of a
polar amino acid at those positions (M205S and M212S) significantly disrupts the native fold of PrP. To understand the role of these Methionines in the
structural stability of PrP in vivo , we expressed PrP-WT, PrP-M205S and PrPM205, 212S in Drosophila. We hypothesized that these mutations would
increase the structural instability of PrP, promoting misfolding and heightening neurotoxicity. First, we found that the Met to Ser mutants did not induce the
progressive locomotor dysfunction and premature death typical of WT PrP. Subsequent to these observations, we performed biochemical assays and these
showed the mutations affect PrP conformation; the flies showed aberrant development in the mushroom bodies, as well as shortened axons at the alpha lobe.
Further results using immunostaining and the antibody 6H4 showed no detection of PrP in the mutants. We also looked at the glycosylation patterns of the
mutant PrP and found that they showed aberrant glycosylation. Also, the mutant PrP contained the N-terminal signal peptide, which is normally detached in
fully processed PrPc. These results demonstrate that the mutant flies carrying the Met to Ser substitutions do not follow the normal PrP biogenesis pathway.
These mutations in the helix 3 seem to induce conformational changes that enhance the formation of ctmPrP, a neurotoxic form of PrP. These findings are
relevant because the ctmPrP topology has been found in patients with prion diseases and may be critical for the conversion of native PrP.
409A
Drosophila β-secretase and the cleavage of the fly Amyloid Precursor Protein are required for glial survival. Bonnie J. Bolkan 1, Tilman Triphan2 ,
Doris Kretzschmar1. 1) CROET, L606, Oregon Hlth & Sci Univ, Portland, OR; 2) Institut für Zoologie III, Universitaet Mainz, 55099 Mainz, Germany.
The presence of Beta-Amyloid (Aβ) containing plaques in the brain is one of the histological hallmarks of Alzheimer’s Disease. Aβ is produced from the
Amyloid Precursor Protein (APP) by β-secretase (or BACE) and γ-secretase cleavage and therefore BACE has become a major focus in studying
Alzheimer’s Disease. In vertebrates, BACE has been shown to affect myelination and neuronal activity, functions that have been associated with the
cleavage of Neuregulin and the β-subunit of a voltage-gated sodium channel, respectively. Here we show that a knockdown of Drosophila BACE (dBACE)
in photoreceptors results in progressive degeneration in the lamina cortex due to a loss of glial cells. Loss of APPL, the sole fly APP protein, suppresses the
degeneration whereas overexpression of APPL enhances the phenotype. An enhancement of the degeneration is even more prominent with a secretion-
deficient form of APPL, which also results in degeneration when expressed alone. We therefore, propose a model in which full-length APPL, which is
expressed in neurons, induces glial death and that dBACE cleavage interrupts this process leading to glial survival.
410B
Assessing the ability of nicotine to increase lifespan and rescue olfactory and motor deficits in parkin loss-of-function Drosophila melanogaster. Lori
M. Buhlman, Raegan P. Chambers, Gerald B. Call. Biomedical Sciences, Midwestern University, Glendale, AZ.
Parkinson’s disease (PD) is the second most common neuromotor degenerative disease, existing in both sporadic and familial forms and affecting about 13
of 100,000 in the US (Van Den Eeden et al., 2002). Drosophila melanogaster is a particularly attractive model for familial PD, as unlike mouse parkin loss-
of-function models, park25/park25 D. melanogaster exhibit many of the pathologies found in familial PD patients, including mitochondrial pathology, motor
deficits and decreased lifespan. Progressive motor deficits found in park25/park25 D. melanogaster are thought to result from mitochondrial pathology that
causes indirect flight muscle degeneration (Greene et al., 2003). Epidemiological studies suggest that tobacco smokers are dose-dependently less likely to
develop PD (Hernan et al., 2001; Grandinetti et al., 1994; Rajput et al., 1987); subsequent in vitro and in vivo studies show that nicotine is protective in
models of sporadic PD (reviewed in Quik et al., 2009). Since olfactory deficits are one of the initial symptoms of PD, we have, for the first time, assessed