Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria type and combined with homocystinuria type
Résumé
An increased reactive oxygen species (ROS) production and apoptosis rate have been associated with several disorders involved in cobalamin metabolism, including isolated methylmalonic aciduria (MMA) type and MMA combined with homocystinuria (MMAHC) type. Given the relevance of p38 and JNK kinases in stress-response, their activation in fibroblasts from a spectrum of patients (, , , and ) was analyzed revealing an increased expression of the phosphorylated-forms, specially in and cell lines that presented the highest ROS and apoptosis levels. To gain further insight into the molecular mechanisms responsible for the enhanced apoptotic process observed in and fibroblasts, we evaluated the expression pattern of 84 apoptosis-related genes by quantitative real-time PCR. An elevated number of pro-apoptotic genes was overexpressed in cells showing a higher rate of apoptosis compared to and control samples. Additionally, apoptosis appears to be mainly triggered through the extrinsic pathway in , while the intrinsic pathway was primarily activated in cells. The differences observed regarding the apoptosis rate and preferred pathway between and patients who both built-up methylmalonic acid, might be explained by the accumulated homocysteine in the group. The loss of MMACHC function in patients might be partially responsible for the oxidative stress and apoptosis processes observed in these cell lines. Our results suggest that ROS production may represent a genetic modifier of the phenotype and support the potential of using antioxidants as a novel therapeutic strategy to improve the severe neurological outcome of these rare diseases.
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