Alzheimer's disease (AD) is a neurodegenerative disorder of the brain and the most common form of senile dementia. The central pathological event leading to AD is thought to be the accumulation of amyloid plaques consisting primarily of a toxic peptide known as amyloid beta peptide (A-beta) in the brain. A-beta is derived from APP by proteolytic processing via the action of two proteases, one of which is gamma secretase. The aberrant action of gamma secretase function underlies the most common early onset familial AD. Gamma secretase resides in a large multi-protein complex with four essential components: presenilin, nicastrin, aph-1 and pen-2. Identifying mechanisms by which gamma secretase activity is regulated should lead to an increased understanding of AD pathogenesis and may provide insight in developing new diagnostic tools and therapeutic targets. ? Drosophila has been used with great success as a molecular genetic tool to identify new genes and study essential biological processes. In Drosophila, the gamma secretase activity and its four essential components are functionally conserved. Thus regulators of gamma secretase identified in Drosophila are likely to be functionally conserved. We have developed a reporter system in the living Drosophila eye that allows us to visualize the endogenous level of gamma secretase activity. Using these flies as a genetic background, we have carried out genetic screens and have identified several candidates to be characterized further.
The specific aims of this proposal are: ? 1. Carry out loss-of-function screens, clone candidate genes and characterize their sites of function. ? 2. Characterize gain-of-function modifiers of gamma-secretase activity. ? 3. Determine how the candidate gene interacts with genes encoding components of gamma-secretase complex, aph-1, pen-2, nicastrin and presenilin ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048396-05
Application #
7488571
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Corriveau, Roderick A
Project Start
2004-04-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2011-08-31
Support Year
5
Fiscal Year
2008
Total Cost
$333,447
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Hartenstein, Volker; Cruz, Louie; Lovick, Jennifer K et al. (2017) Developmental analysis of the dopamine-containing neurons of the Drosophila brain. J Comp Neurol 525:363-379
Gross, Garrett G; Lone, G Mohiddin; Leung, Lok Kwan et al. (2013) X11/Mint genes control polarized localization of axonal membrane proteins in vivo. J Neurosci 33:8575-86
Hay, Bruce A; Chen, Chun-Hong; Ward, Catherine M et al. (2010) Engineering the genomes of wild insect populations: challenges, and opportunities provided by synthetic Medea selfish genetic elements. J Insect Physiol 56:1402-13
Copeland, Jeffrey M; Bosdet, Ian; Freeman, J Douglas et al. (2007) echinus, required for interommatidial cell sorting and cell death in the Drosophila pupal retina, encodes a protein with homology to ubiquitin-specific proteases. BMC Dev Biol 7:82
Chen, Chun-Hong; Huang, Haixia; Ward, Catherine M et al. (2007) A synthetic maternal-effect selfish genetic element drives population replacement in Drosophila. Science 316:597-600
Muro, Israel; Berry, Deborah L; Huh, Jun R et al. (2006) The Drosophila caspase Ice is important for many apoptotic cell deaths and for spermatid individualization, a nonapoptotic process. Development 133:3305-15
Hay, Bruce A; Guo, Ming (2006) Caspase-dependent cell death in Drosophila. Annu Rev Cell Dev Biol 22:623-50