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Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
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phosphorylated by casein kinase I. Whist, substantially phosphorylated TDP is exclusively degraded compared to non-phosphorylated TDP. Furthermore, we
also demonstrated that phosphorylated TDP is indeed mis-localized in the cytosol of fly neurons. Importantly, phosphorylation of disease-associated TDPs
showed more deleterious effect compared to wild type TDP, suggesting phosphorylation plays an important role on TDP proteinopathy. Our studies open a
window to explore the pathogenic role and the biological function of phosphorylated TDP in vitro. We hope that could give a clue for the possible
therapeutic treatment and understand more detailed molecular mechanism of these devastating deposits.
435C
A combinatorial drug cocktail rescues Prion Protein neurotoxicity in flies.
Yan Zhang
1
, Pedro Fernandez-Funez
1,2
, Diego Rincon-Limas
1
. 1) Neurology,
University of Florida, Gainesville, FL; 2) Neuroscience,University of Florida, Gainesville, FL.
Prion diseases are infectious and neurodegenerative disorders in which the normal cellular prion protein (PrP
C
) converts into a misfolded isoform (PrP
Sc
)
with unique biochemical and structural properties that correlate with disease. All prion diseases are fatal, with no effective treatments at this time. In
humans, prion disorders such as Creutzfeldt-Jakob disease present typically with a sporadic origin, where unknown mechanisms lead to the spontaneous
misfolding and deposition of wild type PrP. Expression of wild type PrP in flies induces progressive locomotor dysfunction, spongiform degeneration and
changes in the biochemical and structural properties of PrP. We also found that overexpression of human Hsp70 prevents PrP misfolding and neurotoxicity,
suggesting that Hsp70 could be a therapeutic target in prionopathies. To demonstrate this idea, we fed flies with Hsp90 inhibitors known to result in Hsp70
transcriptional activation. However, none of these treatments resulted in significant effects on PrP accumulation. Then, we tried combinatorial treatments
with compounds that activate Hsp70 by different mechanisms. In these experiments the levels of PrP were reduced by 50 percent, suggesting that elevated
Hsp70 contributed to PrP degradation. In fact, we confirmed that the levels of Hsp70 were significantly elevated by Western blot and quantitative PCR. We
are currently analyzing the functional effects of the combinatorial treatment on PrP-induced neurotoxicity in flies. The results of these experiments will be
discussed in the poster. We propose here that a combinatorial drug treatment can induce sustained high levels of Hsp70 and result in reduced levels of
misfolded PrP. These findings can have important therapeutic consequences for these devastating disorders.
436A
Axonal Transport in Drosophila models of Parkinson’s Disease.
Eric Anderson, Delnessaw Hirpa, Shermali Gunawardena. Department of Biological
Science, The State University of New York at Buffalo, BUFFALO, NY.14260.
Parkinson’s disease (PD) is a common neurodegenerative disease that is characterized by loss of dopaminergic (DA) neurons in the substantia nigra par
compacta and lewy body formation. Thus far more than eight genes with different functions have been implicated in PD. However, little is known about how
these genes contribute to the same PD pathology. Using Drosophila models of PD, we tested the hypothesis that all genes involved in PD have a common
role in axonal transport. We found that expression of human α-synuclein (α-synWT) induces axonal defects in larval segmental nerves. Moreover, Familial
Parkinson’s disease (FPD) mutations in α-syn (Ala30Pro and Ala53Thr) showed enhanced blockages compared to α-synWT. Strikingly, WT and FPD
mutant α-syn genetically interacts with kinesin-1. Preliminary biochemical analysis suggests that α-syn is membrane associated. Further, expression of PINK
(dpink) and DJ1a does not induce axonal defects, but expression of these proteins in the context of reduction of kinesin-1 caused significant axonal defects.
In contrast to α-syn, expression of DJ1a in the context of reduction of dynein caused axonal defects. Together, our results show that although PD proteins
have different functions, they also have a common role in axonal transport. Thus, our observations propose that disruption of the axonal transport pathway
could contribute to early neuropathology observed in Parkinson’s disease.
437B
SERF1 gene function in Drosophila melanogaster.
Swagata Ghosh, Josh Titlow, Robin Cooper, Douglas Harrison, Brian Rymond. Biology, University of
Kentucky, Lexington, KY.
Abstract: SERF1 is a genetic modifier of the autosomal recessive form of Spinal Muscular Atrophy (SMA), the leading genetic cause of human infant
mortality. SERF is well-conserved across species ranging from baker’s yeast to human but its natural biological function is not known in any organism.
Recently it was shown in C. elegans that the loss of SERF/MOAG activity, while phenotypically benign, suppresses amyloid protein toxicity, consistent with
SERF contribution to protein homeostasis (Van Ham et.al, 2010). Here we use a reverse genetic approach to investigate Drosophila SERF1 (dSERF1)
activity. We have created a series of dSERF1 defective backgrounds by combining existing deficiency stocks, imprecise P-element excisions and RNAi co-
expression. The preliminary results show that dSERF1 null mutants are viable and fertile but display locomotor defects that vary with genotype. Gene
complementation and misexpression studies combined with anatomical and neurophysiological analyses are in progress to refine our understanding of
dSERF1 function and investigate the impact of altered dSERF activity on a D. melanogaster model of SMA.
438C
Exposure to fungal volatile organic compound, 1-octen-3-ol leads to induction of NOS-mediated inflammatory response in larval respiratory
system.
Arati A. Inamdar, Joan Bennett. Department of Plant Biology and Pathology, Rutgers, The State University of New Jersey, New Brunswick, NJ.
Indoor air quality significantly influences human health. Today, average person spends about 90% of his time indoors. The growth of fungi and fungal
contaminants pose serious health risks especially in children and older populations. The epidemiological studies support an association between molds and
respiratory tract symptoms in sensitized asthmatic persons and hypersensitivity to pneumonitis in susceptible persons. Moreover, there is suggestive
evidence of association between molds and respiratory illness in otherwise healthy children. We pioneered
Drosophila
model to study the toxic effects of
fungal volatile organic compounds (VOCs), one of the fungal secondary metabolites. Fungal VOCs are emitted as a mixture of several different organic
chemicals. Our inexpensive model seeks to gather data that could establish a causal relationship between fungal VOCs and the respiratory symptoms
reported by occupants of damp and moldy buildings. This approach circumvents the shortcomings of questionnaire-based and correlation studies . We
incorporate
Drosophila
larval tracheal system to determine the modulatory effects of fungal VOCs. Upon exposure to 1-octen-3-ol, the most common fungal
VOCs, larval tracheal linings demonstrated morphological changes. We further determined the induction of inflammatory response mediated by nitric oxide
synthase (NOS) by performing immunostaining and diaphorase staining for activated NOS in tracheal linings. In conclusion, we validate our model to
further dissect the mechanistic studies to explore the causal relationship between te reported respiratory illness and exposure to fungal VOCs.