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REPORT DATE (DD-MM-YYYY)
30-SEP-2007
REPORT TYPE
Annual Report
DATES COVERED (From -To
PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERUniversity of Medicine and Science North Chicago, IL 60064
SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)
U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012
SPONSOR/MONITOR'S REPORT NUMBER(S)
DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited
SUPPLEMENTARY NOTES
ABSTRACTPurpose: Alternative splicing is responsible for producing several products from a single transcript and can cause pathogenic changes in RNA in neurodegenerative disease. This proposal tests the hypothesis that regulation of normal splicing is disrupted in Parkinson's disease (PD). Scope: Experiments are designed to determine splicing products in the brain and blood of experimental MPTP models of PD and the blood of newly diagnosed PD patients, who are not yet on dopamine therapy. The overall goal is to use splice variants as biomarkers to identify individuals at risk for PD. To date, we have identified and quantified alternatively spliced transcripts for several candidate genes in MPTP models of PD. We have also obtained IRB permission to study splicing factors in the blood of newly diagnosed PD patients. Major Findings: Mice treated acutely and chronically with MPTP show a shift in the ratio of FosB, RGS9, AChe and Ania6 splice variants in the striatum and blood. Gene expression (in situ hybridization) studies are in progress to localize the variants in the brain. Progress in the second year in cludes 3 abstracts, one published article, a second article submitted and an article in preparation.
SUBJECT TERMS
IntroductionIn humans, non-human primates and mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes pathological damage similar to that observed in Parkinson's disease (PD) (Langston et al., 1984). The active metabolite of MPTP is MPP+ and this blocks the respiratory chain in mitochondria resulting in increased free radicals and ultimately cell death....