Expression analysis of novel striatal-enriched genes in Huntington disease

Abstract

Selective degeneration of striatal neurons is a pathologic hallmark of Huntington disease (HD). The exact mechanism(s) behind this specific neurodegeneration is still unknown. Expression studies of diseased human post-mortem brain, as well as different mouse models exhibiting striatal degeneration, have demonstrated changes in the expression of many important genes with a large proportion of changes being observed in the striatal-enriched genes. These investigations have raised questions about how enrichment of particular transcripts in the striatum can lead to its selective vulnerability to neurodegeneration. Monitoring the expression changes of striatal-enriched genes during the course of the disease may be informative about their potential involvement in selective degeneration. In this study, we analyzed a Serial Analysis of Gene Expression (SAGE) database (www.mouseatlas.org) and compared the mouse striatum to 18 other brain regions to generate a novel list of striatal-enriched transcripts. These novel striatal-enriched transcripts were subsequently evaluated for expression changes in the YAC128 mouse model of HD, and differentially expressed transcripts were further examined in human post-mortem caudate samples. We identified transcripts with altered expression in YAC128 mice, which also showed consistent expression changes in human post-mortem tissue. The identification of novel striatal-enriched genes with altered expression in HD offers new avenues of study, leading towards a better understanding of specific pathways involved in the selective degeneration of striatal neurons in HD.

Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites

“…Notably, increased levels of 3-HK and QUIN have been measured in the neostriatum and cortex of patients with early stage HD (15), and these changes are associated with an up-regulation of IDO1 transcription (38) and a reduction in the activity of KAT, which is critical for KYNA synthesis (17). These data in patients with HD are supported by observations in HD mice, which show increased cerebral KMO activity (39).…”

The kynurenine pathway and neurodegenerative disease

“…In HD mouse models, levels of 3-HK and QUIN are also increased in the brain, and correlate with the onset of HD phenotypes [61]. The upregulation of IDO1 transcription has been observed in the YAC128 HD mouse model [62] and suggests a cause for the increased ratio of L-KYN/TRP in the blood of HD patients [63] [64]. Increased KMO activity has also been implicated as the source of elevated brain 3-HK levels in mice [65].…”

Amyloid in neurodegenerative diseases: Friend or foe?

“…An equally challenging enigma in neurodegenerative amyloidoses is the cause of selective vulnerability of certain neuronal populations. Each neurodegenerative disorder affects a specific subset of neurons even though the disease associated protein is often present in many cells throughout the brain and the rest of the body [7]. This phenomenon may be a result of interactions between an array of intracellular factors which have both positive and negative influences on the cells ability to buffer accumulation of potentially toxic proteins [8, 9].…”