A1M, Hb and tryptophan metabolism in R6/2 mouse model of Huntington’s disease

Sammanfattning: Neurotoxic metabolites generated from tryptophan metabolism are increasingly regarded as a pathogenic mechanism in neurological and psychiatric disease including Huntington’s disease (HD). Specifically, the tryptophan-derived neurotoxin 3-hydroxykynurenine (3-HK) accumulates in HD brain and is capable of damaging neurons through excessive ROS-production and oxidative stress. The protein A1M, alpha-1-microglobulin, is an endogenous scavenger of radicals and heme that also has been shown to form covalent adducts with 3-HK. ROS, hemoglobin and heme up-regulates A1M expression, but whether a similar relationship exists between A1M and 3-HK is not known. We hypothesized that A1M would be up-regulated in a mouse model of HD, R6/2 mice, as a defense against 3-HK production and radical stress. We also wanted to study the expression of the two rate limiting enzymes of the KP, Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) as they are regulated by different mechanisms, IDO primarily being up-regulated by IFN-gamma under inflammatory conditions. We also measured serum concentration of Hb, after a previous finding that plasma hemoglobin levels are elevated and correlates with disease severity in HD patients. Protein expression in R6/2 mice and healthy controls was measured using real-time PCR. Serum concentrations of A1M and Hb were measured using the ELISA method. We did find a tendency towards higher A1M serum concentration in the R6/2 group, although not statistically significant, and also significantly higher concentrations of Hb in serum. We did not find a significant up-regulation of A1M-mRNA in brain, liver or kidney in R6/2 mice as compared to healthy controls. Serum levels of Hb tended to correlate positively with A1M levels, but the correlation did not reach statistical significance. We also found a tendency towards increased expression of the enzyme TDO in the R6/2 mice. IDO was not detected in either group. Our findings regarding A1M and hemoglobin in HD were in line with previous findings in HD patients. The relationship between A1M and the kynurenine pathway in HD still warrants further investigation.