The kynurenine pathway is currently of intense interest due to its potential role in the pathogenesis and treatment of several important neurological disorders including Alzheimer’s (AD) and Huntington’s diseases (HD). The pathway is the major route of tryptophan degradation in mammals, with several of the intermediate metabolites having neuroactive properties. In particular kynurenic acid is neuroprotective, while 3-hydroxykynurenine and quinolinic acid are neurotoxic. One of the key enzymes in the pathway, kynurenine 3-monooxygenase (KMO) has been identified as modifying the Huntington disease phenotype in yeast, Drosophila and mouse model systems. This has led to the recent finding that KMO inhibitors ameliorate the symptoms of both HD and AD in mouse models, and work is progressing to develop therapeutic agents.
In the brain the KMO gene is expressed mainly in microglia, but otherwise little is known about the control of its expression. Human KMO lies on Chromosome 1 next to the Opsin 3 gene, with some transcripts of the two genes overlapping, potentially indicating a form of antisense-mediated silencing. Further analysis of the role of transcription factors, DNA methylation and genetic variation on KMO are warranted. The project will investigate factors that control the expression of transcripts of the two genes in neuronal and microglial cell lines, with an aim to better understand the role of KMO in normal and disease states.
The specific aims of this project are:
i. To investigate the expression of the various KMO and OPN3 transcripts in cell lines
ii. To experimentally verify whether antisense-mediated silencing of KMO occurs
iii. To determine the genetic and epigenetic modifiers of KMO expression.