Two hallmarks of Alzheimer's Disease (AD) are increased expression and aggregation of an insoluble peptide, derived through the cleavage of the amyloid precursor protein (APR) and hyperphosphorylation of the microtubule associated protein tau. Both processes are thought to contribute to cell death and inhibiting expression of both proteins is effective in ameliorating AD symptoms. The major mechanism whereby translation of eukaryotic mRNAs is initiated is through a cap-binding complex. The preinitiation complex, however, can also bind sites on the mRNA, termed internal ribosomal entry sites (IRESes) and initiate translation in a cap-independent manner. IRESes have been most extensively characterized in picornaviral mRNAs and little is known about IRESes in cellular mRNAs. IRES-dependent translation is unaffected or promoted by cellular stress. Interestingly, both vascular insults including ischemia and increased levels of iron in the central nervous system are two stressful stimuli that may predispose individuals or enhance the progression of AD. Indeed, in response to ischemia and iron toxicity, there is a decrease in global protein synthesis, but the synthesis of APR increases. Our working hypothesis is that the APP and tau 5' UTRs contain an IRES and that internal initiation is the primary mechanism utilized for their translation. In addition, we propose that IRES-dependent APP synthesis is upregulated by iron and ischemia. Accordingly our goals are 1) determine if the APP and tau mRNAs are translated through IRESes located in their 5' UTR, 2) identify intracellular signaling pathways, transcriptional elements, and gene products that contribute to basal and ischemia/iron induced IRES activity, 3) identify RNA binding proteins crucial for APP and tau IRES activity, and 4) characterize the interaction between these proteins and the APP and tau IRESes. The proposed experiments will determine the mechanism of protein synthesis contributing to APP and tau protein synthesis in AD. Understanding the molecular basis of this translational mechanism will open new avenues for rationale drug design for the therapeutic intervention of individuals with AD. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG028156-01A2
Application #
7317449
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Snyder, Stephen D
Project Start
2007-07-15
Project End
2012-04-30
Budget Start
2007-07-15
Budget End
2008-04-30
Support Year
1
Fiscal Year
2007
Total Cost
$312,379
Indirect Cost
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Veo, Bethany L; Krushel, Les A (2009) Translation initiation of the human tau mRNA through an internal ribosomal entry site. J Alzheimers Dis 16:271-5
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Dobson, Tara; Kube, Erika; Timmerman, Stephanie et al. (2008) Identifying intrinsic and extrinsic determinants that regulate internal initiation of translation mediated by the FMR1 5'leader. BMC Mol Biol 9:89