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Poster Full Abstracts - Drosophila Models of Human Diseases
Poster board number is above title. The first author is the presenter
248
neurodegeneration and life span reduction. These flies also exhibit aggregate formation and age-dependent vacuolization of the brain. By employing glia
subset-specific GAL4 drivers we have identified the Astrocyte glia as the critical glia subtype necessary for neuroprotection. We will present data from
confocal microscopy, transmission electron microscopy and behavioral analyses. These data suggest a vital role for glia in neuroprotection, as well as a
regulatory role for the APC/C in glial differentiation.
431B
Integrating Human and Fly Genetics to Understand Alzheimer's Disease Susceptibility.
Joshua M. Shulman
1,2
, Selina Imboywa
1,2
, Allison E.
Diamond
1,2
, Portia I. Chipendo
1,2
, Philip L. De Jager
1,2
, Mel B. Feany
1,2
. 1) Brigham and Women's Hospital, Boston, MA; 2) Harvard Medical School,
Boston, MA.
BACKGROUND: Advances in human genetics have made the discovery of susceptibility loci for Alzheimer’s disease (AD) a reality. The critical next step
will be to determine the responsible genes and mechanisms. We are therefore integrating the results of human genome-wide association studies (GWAS)
with a simple but powerful functional screen in existing
Drosophila
models of AD. METHODS: From published GWAS, 130 candidate AD susceptibility
genes achieved significant (
p
<5x10
-8
) or suggestive (
p
<10
-4
) associations, nominating 89 conserved fly gene orthologs for further study. Lines predicted to
activate or disrupt gene function were screened for enhancement or suppression of the rough eye phenotype produced by expression of human Tau or
Amyloid-Beta (Aβ), which form neurofibrillary tangles and amyloid pathology in AD. Selected genes were also evaluated for impact on age-dependent,
Tau-induced neurodegeneration in the brain. RESULTS: Our ongoing screen has identified 11 novel genes demonstrating robust interactions with Tau or Aβ
neurotoxicity
in vivo
. Disruption of the fly integrin receptor
scb
(orthologous to human
ITGAM
and
ITGA9
) or the integrin modulators,
Fit1/2
(orthologous
to the kindlin,
FERMT2
), enhanced Tau toxicity. We also find that gain- and loss-of-function in
cindr
, a regulator of actin dynamics and the ortholog of
CD2AP
, reciprocally suppress and enhance Tau retinal toxicity, and
cindr
also modifies Tau-induced neurodegeneration. Our cross-species strategy
highlights several additional molecular pathways, including kinases (
EPHA1
/
Eph
) the microtubule cytoskeleton (
MAST4
/
CG6498
), and RNA-binding
proteins (
SNRPN
/
SmB
). CONCLUSIONS: Based on associations with human disease and functional interactions in
Drosophila
, we identify integrin-
mediated adhesion and several other cellular pathways as potentially important in AD susceptibility. Integrating human and fly genetics is likely to be a
powerful approach to enhance AD gene discovery in the future.
432C
Effects of HDAC inhibitor treatment on motor deficits and lethality in a
Drosophila
model of Parkinson's disease.
Robyn St. Laurent, S. Tariq
Ahmad. Department of Biology, Colby College, Waterville, ME.
Parkinson’s disease (PD) is a neurodegenerative disorder affecting dopaminergic neurons in the substantia nigra and characterized by debilitating motor
impairment. In
Drosophila
, chronic exposure to the pesticide rotenone, known to selectively deteriorate dopaminergic neurons, produces PD-like motor
deficits. Genetic models of Huntington’s disease in
Drosophila
have similar motor deficits. The deficits seen in Huntington’s, however, are caused by an
expansion of a glutamine repeat in the Htt protein resulting in degeneration of neurons in the striatum. These motor deficits are attenuated by treatment with
histone deacetylase (HDAC) inhibitors such as sodium butyrate. This study aims to examine the effects of the novel treatment of HDAC inhibitors on motor
deficits and lethality in a rotenone-induced PD model using
Drosophila
. 1-7 day old
Drosophila melanogaster
wildtype flies (
Canton-S
) were fed rotenone
at 25 μM or 250 μM concentrations for 7 days. Motor functioning was tested using a negative geotactic assay to measure climbing and flight abilities.
Exposure to 250 μM rotenone caused motor deficits and increased lethality compared to control and 25 μM treatment. Preliminary findings from
simultaneous sodium butyrate and rotenone exposure suggest an improvement of motor deficits and lethality compared to rotenone exposure alone. We are
currently characterizing the mechanism of sodium butyrate-mediated improvement in the rotenone-induced PD model.
433A
TDP-43 and FUS proteinopathies: biochemical studies and animal models.
Mengxue Yang
1,2
, Kazuo Fushimi
1
, Xiaoping Chen
1
, Tanya Monahiem
1
,
Jianghong Liu
2
, Li Zhu
2
, Jane Wu
1,2
. 1) Northwestern University, Chicago, IL; 2) Institute of Biophysics, CAS, China.
Recent studies have discovered mutations in genes encoding RNA binding proteins, TAR-DNA binding protein 43 (TDP-43) and fused in sarcoma/
translocated in liposarcoma (FUS/TLS) in patients with TDP-43 or FUS proteinopathies, including Ub+ frontotemporal lobar degeneration (FTLD-u) and
amyotrophic lateral sclerosis (ALS). To elucidate the pathogenic mechanisms, we have begun to examine molecular and biochemical features of TDP-43 and
FUS in cultured cells. We have established transgenic fly models of these proteinopathies by expressing wild type (Wt) or ALS-mutant forms of human
TDP-43 or FUS proteins respectively.
We have begun to systematically compare molecular pathology induced by expression of Wt and ALS-mutant TDP-43 in cultured cells or transgenic flies.
Expression of the ALS-associated A315T mutant remarkably accelerates neurodegeneration in flies. The A315T mutant significantly enhances neurotoxicity
and increases the formation of aberrant TDP-43 species. The C-terminal domain of TDP-43 shows sequence similarity to the prion protein. Synthetic TDP-
43 peptides flanking amino acid residue 315 form amyloid fibrils in vitro and cause axonal damage and neuronal death in cultured neurons. Our work
identifies an amyloidogenic and neurotoxic region in the C-terminal domain of TDP-43 flanking amino acid residue 315. These experiments reveal
similarities between TDP-43 and prion proteins in their peptide sequences and biochemical properties. Our work suggests that decreasing formation of
neurotoxic TDP-43 species and enhancing clearance of such derivatives may have therapeutic potentials. We have begun to characterize cells and flies
expressing Wt or ALS-mutant forms of FUS. Flies expressing ALS-mutant FUS show accelerated and more severe phenotypes of age-dependent progressive
neurodegeneration, recapitulating key features of human FUS proteinopathy. The relevance to human diseases and potential applications in developing new
therapies will be discussed.
434B
Exploring the Pathogenic Role of Phosphorylated TDP in Drosophila Nervous System.
Po-An Yeh, Pang-hsien Tu. Biomedical Sciences, Taipei.
TAR DNA binding protein (TDP) has been broadly shown as a main component of ubiquitinated deposits in the nervous system of patients with
frontaltemporal lobar degeneration or amyotrophic lateral sclerosis. Although hyperphosphorylation of TDP is also present in those diseases, the function
and consequence of TDP phosphorylation remain unclear. In this study, using Drosophila melanogaster as a model system, TDP was shown to be