Alzheimer's disease is a devastating and common disease of the central nervous system, and studies of familial forms have identified a number of loci that are implicated in the development of the disease. The C. elegans model that is the subject of this proposal is based on the finding that the sel-12 gene encodes a protein that is highly similar to two genes associated with early-onset familial Alzheimer's disease. The remarkable conservation of the predicted C. elegans and human proteins suggests that their functions are likely to be conserved as well. Furthermore, nearly all mutations associated with early-onset familial Alzheimer's disease in people alter amino acids that are identical in SEL-12. The Principal Investigator hopes to bring the tools of classical and molecular genetic studies in C. elegans to bear on fundamental issues of the structure and function of SEL-12 and its human homologs.
The specific aims of this proposal are: I.A basic characterization of sel-12. The proposed experiments will directly test the functional equivalence of S182, STM2 and SEL-12. Other experiments are concerned with establishing the null phenotype, characterizing the expression pattern, identifying behavioral defects, generating antibodies to SEL-12, and identifying C. elegans genes that are highly similar to sel-12. II. To engineer sel-12 transgenes [""""""""sel-12(Alz)""""""""] containing alterations associated with early-onset familial Alzheimer's disease. The proposed experiments are concerned with the generation and genetic and phenotypic analyses of sel-12(Alz) transgenic lines. III. The identification and characterization of extragenic suppressors of sel-12(ar171) and sel-12(Alz). The proposed experiments are concerned with the reversion of sel-12(ar171) and sel-12(Alz) mutants, and genetic and molecular analyses of suppressor genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035556-03
Application #
2750949
Study Section
Neurology C Study Section (NEUC)
Program Officer
Oliver, Eugene J
Project Start
1996-09-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Physiology
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Katic, Iskra; Vallier, Laura G; Greenwald, Iva (2005) New positive regulators of lin-12 activity in Caenorhabditis elegans include the BRE-5/Brainiac glycosphingolipid biosynthesis enzyme. Genetics 171:1605-15
Karp, Xantha; Greenwald, Iva (2004) Multiple roles for the E/Daughterless ortholog HLH-2 during C. elegans gonadogenesis. Dev Biol 272:460-9
Karp, Xantha; Greenwald, Iva (2003) Post-transcriptional regulation of the E/Daughterless ortholog HLH-2, negative feedback, and birth order bias during the AC/VU decision in C. elegans. Genes Dev 17:3100-11
Jarriault, Sophie; Greenwald, Iva (2002) Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12/Notch signaling in C. elegans. Genes Dev 16:2713-28
Wen, C; Levitan, D; Li, X et al. (2000) spr-2, a suppressor of the egg-laying defect caused by loss of sel-12 presenilin in Caenorhabditis elegans, is a member of the SET protein subfamily. Proc Natl Acad Sci U S A 97:14524-9
Levitan, D; Greenwald, I (1998) LIN-12 protein expression and localization during vulval development in C. elegans. Development 125:3101-9
Wu, G; Hubbard, E J; Kitajewski, J K et al. (1998) Evidence for functional and physical association between Caenorhabditis elegans SEL-10, a Cdc4p-related protein, and SEL-12 presenilin. Proc Natl Acad Sci U S A 95:15787-91
Levitan, D; Greenwald, I (1998) Effects of SEL-12 presenilin on LIN-12 localization and function in Caenorhabditis elegans. Development 125:3599-606
Li, X; Greenwald, I (1998) Additional evidence for an eight-transmembrane-domain topology for Caenorhabditis elegans and human presenilins. Proc Natl Acad Sci U S A 95:7109-14
Wen, C; Metzstein, M M; Greenwald, I (1997) SUP-17, a Caenorhabditis elegans ADAM protein related to Drosophila KUZBANIAN, and its role in LIN-12/NOTCH signalling. Development 124:4759-67

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