Establishment of animal models to determine environmental factors involved in the brain integrity

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16580075
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied biochemistry
• Research Institution: Aoyama Gakuin University
• Principal Investigator: FUKUOKA Shinichi Aoyama Gakuin University, College of Science and Engineering, Professor, 理工学部, 教授 (20183923)
• Co-Investigator(Kenkyū-buntansha): SHIBATA Katsumi The University of Shiga Prefecture, Department of Life-style Studies, Professor, 人間文化学部, 教授 (40131479)
• Project Period (FY): 2004 – 2005
• Keywords: quinolinate / neurotoxin / Huntington's disease / tryptophan / NMDA

Research Abstract

[Purpose] Quinolinic acid (QA) is an intermediate metabolite in the tryptophan pathway. It has been known that the brain level of QA is risen in neurodegenerative disorders, such as Huntington's disease (HD). The neurologic deficit and the degradation at the levels of neurotransmitter are caused in rat brain by the intrastriatal administration of QA, which acts as an N-methyl-D-aspartate receptor (NMDAR) antagonist to show the endogenous excitotoxin. These observations propound a hypothesis, in which QA causes various neurodegenerative disorders, such as HD, AD and AIDS dementia complex (quinolinic acid hypothesis). The molecular mechanism for the elevation of QA level in brain and the mechanism of action of QA-induced neurodegeneration are unclear. In this study, we tried to show the molecular mechanism for the elevation of QA level and the mechanism of action of QA-induced neurodegeneration in HD.
[Results and Discussion] We used HD transgenic mice (HD mice) into which highly expanded CAG repeats in exon 1 of human huntingtin gene were introduced for this study. Although HD mice normally developed by 8 weeks of age, the weight was decreased from 8 weeks age and choreiform-like movement, which was characteristic symptoms of HD, was expressed at 11 weeks age. Firstly, we measured enzyme activities for tryptophan pathway in liver and kidney of HD mice to investigate on any derangements in tryptophan metabolism. In liver of HD mice, activity of 3-HAO, which is responsible for QA synthesis, was significantly increased and activity of ACMSD, which inhibits QA production, was significantly decreased. On the other hand, activity of QPRT, which is responsible for QA catabolism, was unchanged. We considered that decreasing of ACMSD activity and increasing of 3-HAO activity induce elevation of QA level in urine in which the metabolite level in urine was correlated with those in blood, so we measured urinary excretion of tryptophan metabolites in HD mice. As a result of measurement, urinary excretion of QA was significantly increased in HD mice. These results suggest that the derangement of tryptophan metabolism in HD mice induce the elevation of QA level and show a possibility that metabolic derangement in the brain is also derived. We therefore analyzed any changes in gene expression patterns in cerebral cortex, cerebellum, striatum and hippocampus of HD mice using real-time PCR. In HD mice, mRNA expression levels of QPRT and ACMSD were equal to or lower than those in wild type mice. We speculated that decreasing at gene expression levels of QPRT and ACMSD induced elevation of brain QA level.
[Conclusion] These results suggest that elevation of QA level in brain of HD mice is caused by decreasing at gene expression levels of QPRT and ACMSD. We proposed that the derangement in tryptophan metabolism in HD caused at least in part by the elevation of brain QA levels.