The goal of this proposal is to determine the normal function of synelfin, a neuronal protein abundant in the adult vertebrate telencephalon. Synelfin has been independently isolated from several species, including humans, where it has been referred to as NACP (the Non-Amyloid beta-Component Precursor) to indicate its relationship to a novel peptide recently purified from amyloid plaques in Alzheimer Disease (AD). Studies in songbirds suggest that this highly-conserved protein has a specific but yet-undefined role in the normal regulation of synaptic plasticity. To gain insight into the normal function of synelfin, three research aims are proposed: 1) conduct biochemical studies to test the hypothesis that synelfin has a functional relationship to apolipoproteins, as suggested by observation of conserved structural features. Normal and mutated forms of synelfin protein will be expressed in E.coli and analyzed for their interactions with phospholipids, using the well-characterized behavior of apoliopoproteins as a point of comparison. 2) determine the structural elements in the protein responsible for its accumulation at presynaptic terminals. Mutated DNA constructs will be introduced into primary cultured hippocampal neurons, and the encoded proteins will be localized by immunofluorescence. These studies may give insight into the apparent modular structure of the protein, and help in the design of experiments to identify other proteins with which synelfin interacts. 3) overexpress the synelfin protein in transgenic mice and assay the effect on neuroanatomy and neurological function. This will test the hypothesis whether a constitutive increase in synelfin will promote the development of Alzheimer-like neuropathology, or alter developmental or behavioral processes that depend upon neural plasticity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013762-02
Application #
2607668
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (01))
Project Start
1997-01-15
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Hasadsri, Linda; Kreuter, Jörg; Hattori, Hiroaki et al. (2009) Functional protein delivery into neurons using polymeric nanoparticles. J Biol Chem 284:6972-81
Woods, Wendy S; Boettcher, John M; Zhou, Donghua H et al. (2007) Conformation-specific binding of alpha-synuclein to novel protein partners detected by phage display and NMR spectroscopy. J Biol Chem 282:34555-67
Payton, Jacqueline E; Perrin, Richard J; Woods, Wendy S et al. (2004) Structural determinants of PLD2 inhibition by alpha-synuclein. J Mol Biol 337:1001-9
Perrin, R J; Payton, J E; Barnett, D H et al. (2003) Epitope mapping and specificity of the anti-alpha-synuclein monoclonal antibody Syn-1 in mouse brain and cultured cell lines. Neurosci Lett 349:133-5
George, Julia M (2002) The synucleins. Genome Biol 3:REVIEWS3002
Perrin, R J; Woods, W S; Clayton, D F et al. (2001) Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J Biol Chem 276:41958-62
Perrin, R J; Woods, W S; Clayton, D F et al. (2000) Interaction of human alpha-Synuclein and Parkinson's disease variants with phospholipids. Structural analysis using site-directed mutagenesis. J Biol Chem 275:34393-8
Clayton, D F; George, J M (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58:120-9
Clayton, D F; George, J M (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease. Trends Neurosci 21:249-54
Davidson, W S; Jonas, A; Clayton, D F et al. (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443-9

Showing the most recent 10 out of 11 publications