Kynurenic Acid Synthesis in Mouse Brain

Virginia Polytechnic Inst And St Univ, Blacksburg VA

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Abstract

DESCRIPTION (provided by applicant): It is currently estimated that in 2050, the cost of treating the aging population for dementia caused by various neurodegenerative diseases will consume the entire gross national product of the industrialized countries. Consequently, effective preventive measures and treatments for neurodegenerative diseases must be urgently developed. In mammalian brains, glutamate-mediated neurotransmission is responsible for basal excitatory synaptic transmission and many forms of neuroplastic responses. However, events that substantially increase the level of glutamate-mediated excitatory activity often induce excitotoxic neuronal injury, leading to the development of neurodegenerative diseases. Kynurenic acid (KYNA, a tryptophan metabolite) acts as a glutamate receptor antagonist and is believed to play a role in modulating glutamate-mediated neurotransmission. Deficiency or overaccumulation of brain KYNA has been linked to a variety of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases, suggesting that failure to maintain physiological levels of brain KYNA could be one of the causative factors of neurodegenerative diseases. KYNA is produced by the kynurenine aminotransferase (KAT)-catalyzed transamination of kynurenine. Because KYNA cannot pass through the blood brain barrier, it must be produced in the brain. Based on the intimate relationship between abnormal brain KYNA levels and neurodegenerative diseases, brain KATs have been considered potential targets for regulating human brain KYNA synthesis and preventing neurodegenerative diseases. To target KATs for brain KYNA regulation, however, it is necessary to determine the number of KATs present, the specific contribution of each to brain KYNA production, and their structural characteristics. We hypothesize that brain KYNA synthesis is the collective contribution of a number of aminotransferases and that the specific contribution of individual KATs differs depending on their relative content and localization in the brain as well as their overall catalytic efficiency to kynurenine and other substrates. The specific aims of this research proposal are: (1) to analyze the substrate specificity and catalytic efficiency of the currently identified KATs to kynurenine and other substrates through the expression and extensive biochemical characterization of their recombinant proteins, (2) to determine the identity, relative amount and cellular localization of brain KATs through antigen- antibody based techniques using mice as the model species, and (3) to establish the structure/function relationship of KATs through macromolecular crystallography. Laboratory mice are widely considered the model species for studying human diseases because mice and humans share the vast majority of their physiological and pathological features. It is anticipated that the results from the planned research will contribute to our understanding of the human brain KYNA biosynthesis and regulation, which may provide insight regarding strategies towards maintaining normal KYNA levels in the human brain. PUBLIC HEALTH RELEVANCE: Kynurenic acid (KYNA) is a nonselective antagonist of excitatory amino acid receptors and involved in modulating glutamatergic neurotransmission in mammalian brains. Abnormal concentrations of brain KYNA have been linked to a number of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. The research described in this proposal investigates physiology and biochemistry of enzymes responsible for the production of brain KYNA using mice as model species.