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Full Abstracts – DROSOPHILA MODELS OF HUMAN DISEASE
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20
Drosophila - a useful model for anti-amyloid drug development.
Daniel Segal
1
, Roni Scherzer-Attali
1
, Ronit Shaltiel-Karyo
1
, Sivan Peled
1
, Moran
Frenkel-Pinter
1
, Dorit Farfara
2
, Dan Frenkel
2
, Ehud Gazit
1
. 1) Molecular Microbiol & Biotech, Tel Aviv Univ, Tel Aviv; 2) Neurobiology, Tel Aviv Univ,
Tel Aviv.
Drosophila offers an attractive model for drug development which can reduce the use of vertebrates and cut costs. Our recent work on developing
inhibitors of amyloid assembly exemplifies this strategy. We have previously identified a key role of aromatic residues in the molecular recognition and self-
assembly leading to the formation of various amyloid assemblies. Aromatic interactions provide selectivity as well as stability to the interacting molecules.
Our strategy is to use small aromatic molecules that would bind the aromatic residues of the beta-amyloid (Aβ) monomers in Alzheimer's disease (AD)
thereby inhibit the early steps of the molecular recognition and structural transition of the monomers which lead to the formation of the toxic amyloid
species. We have synthesized a series of N-linked tryptophan-modified quinones and screened them for anti-Aβ activity. Two compounds, NQTrp and Cl-
NQTrp, were most effective. They inhibit Aβ oligomerization and fibrillization in vitro and reduce the cytotoxic effect of Aβ oligomers towards cultured
cells. NMR spectroscopy and molecular dynamics simulations provide a mechanistic basis for the activity of these compounds. When fed to Drosophila
expressing Aβ in their nervous system, these compounds alleviated their AD-related symptoms while having no effect on control flies. When injected
intraperitonealy to 5xFAD transgenic acute AD mice they led to specific and significant improvement of their cognitive behavior, dramatic reduction in the
level of both soluble and insoluble Aβ in their brain extracts and marked decrease in Aβ deposition in their brains. The compounds can cross the blood-
brain-barrier and have no adverse effects. We have also shown that β-synuclein-derived peptidomimetics designed to inhibit the toxic amyloid assembly of
α-synuclein in Parkinson disease (PD) have marked remedial effect in Drosophila expressing α-synuclein in their brain which serve as an established model
for PD.
21
Creating an epileptic fly by tipping the balance of
prickle
isoforms.
Salleh Ehaideb
1
, Atsushi Ueda
1
, Alexander G Bassuk
1
, Chun-Fang Wu
1
, J Robert
Manak
1,2
. 1) Dept of Biology, Univ of Iowa, Iowa City, IA; 2) Dept of Pediatrics, Univ of Iowa, Iowa City, IA.
prickle
participates in the non-canonical WNT signaling/planar cell polarity (PCP) pathway. We previously reported that fly
prickle
mutants are seizure-
prone, and that mutations in Prickle orthologues are associated with seizures in flies, mice and humans.
prickle
encodes two adult isoforms,
prickle
(
pk
) and
spiny legs
(
sple
). Strikingly, flies heterozygous for the
pk
sple1
mutation display pronounced seizures even though no planar cell polarity defects are visible,
suggesting that the PCP and seizure phenotypes can be genetically separated. We now report that
pk
pk
mutations are actually protective against seizures,
consistent with PCP data that
pk
and
sple
act antagonistically towards one another. Additionally,
pk
sple
mutant larvae have both anatomical and
electrophysiological neuronal defects. Finally, targeted overexpression of the
pk
pk
isoform in motor neurons and muscles (which recapitulates the imbalance
of
pk
vs
sple
isoforms seen in the
pk
sple
heterozygote) strongly induces fly seizures in an otherwise wild-type fly. These results likely pinpoint the tissues
involved in human epilepsy in patients with Prickle mutations.
22
microRNAs Orchestrate Muscular Dystrophy in Drosophila.
April K. Marrone, Halyna R. Shcherbata. Laboratory of Gene Expression and Signaling,
Max Planck Institute for Biophysical Chemistry, Goettingen, Germany.
In Drosophila, like in humans, Dystrophin Glycoprotein Complex (DGC) deficiencies cause a life span shortening disease, associated with muscle
dysfunction and cognitive impairment. We have shown that in addition to mutations in DGC main components Dystrophin (Dys) or Dystroglycan (Dg),
stress can induce muscle degeneration and accelerate age-dependant muscular dystrophy even in wild type animals. In an effort to explore mechanisms by
which stress can cause dystrophy we have turned to microRNA biogenesis and have performed a microarray screen on whole adult flies to determine
misregulation in genetic mutants for Dys and Dg and high temperature stressed animals. We have been able to define three categories of misexpressed
microRNAs; stress derived, Dys and/or Dg dependent and those that are altered in stress and mutant situations. In this screen we were able to detect altered
microRNA levels not only in dystrophic muscle as has been done previously in mammals, but in the brain and nervous system. Since abnormal functioning
of Dg causes congenital muscular dystrophies that are associated with brain defects and the function of the DGC in the nervous system has not been fully
defined, we have focused on misregulated microRNAs that have the potential to target Dg in this tissue. Interestingly, we found that Dg isoforms can have
variant 3’UTRs that allow for specific regulation by certain microRNAs. The plethora of miRNAs implicated in the DMD pathology present a substantial
and complex level of regulation that opens diverse avenues for future research and therapies.