Alternative pre-mRNA splicing is a critical step in gene expression and regulation. Accumulating evidence indicates that pre-mRNA splicing defects and aberrant splicing are associated with a number of neurodegenerative disorders. For example, aberrant alternative splicing of tau gene due to intronic mutations has been found in certain inherited forms of dementia. This proposal aims to investigate the role of alternative splicing in neurodegeneration by using a tau minigene model system that we have established. We plan to use molecular and biochemical approaches to study the regulatory mechanism underlying tau alternative splicing. We have established both in vitro biochemical assays and cell culture system to examine the effect of newly identified and known splicing regulators on tau alternative splicing. Our preliminary studies have revealed that certain alternative splicing factors may play a role in regulating tau alternative splicing. A primary neuronal culture system has also been set up to investigate the role of identified factors in neuronal cell death. Molecular dissection of cis- and trans-acting elements important for tau alternative splicing will not only help in understanding the basic mechanism controlling tau alternative splicing but also reveal new players in the pathogenesis of neurodegeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG017518-01
Application #
6031515
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Oliver, Eugene J
Project Start
1999-09-30
Project End
2004-07-31
Budget Start
1999-09-30
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Mordes, Daniel; Yuan, Liya; Xu, Lili et al. (2007) Identification of photoreceptor genes affected by PRPF31 mutations associated with autosomal dominant retinitis pigmentosa. Neurobiol Dis 26:291-300
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Sobrido, Maria-Jesus; Miller, Bruce L; Havlioglu, Necat et al. (2003) Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia. Arch Neurol 60:698-702

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