Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects.

[homocystinuria without methylmalonic aciduria]

Oxidative stress has been described as a putative disease mechanism in pathologies associated with an elevation of homocysteine . An increased reactive oxygen species (ROS ) production and apoptosis rate have been associated with several disorders of cobalamin metabolism , particularly with methylmalonic aciduria (MMA ) combined with homocystinuria cblC type . In this work , we have evaluated several parameters related to oxidative stress and apoptosis in fibroblasts from patients with homocystinuria due to defects in the MTR , MTRR , and MTHFR genes involved in the remethylation pathway of homocysteine . We have also evaluated these processes by knocking down the MTRR gene in cellular models , and complementation by transducing the wild-type gene in cblE mutant fibroblasts . All cell lines showed a significant increase in ROS content and in MnSOD expression level , and also a higher rate of apoptosis with similar levels to the ones in cblC fibroblasts . The amount of the active phosphorylated forms of p 38 and JNK stress-kinases was also increased . ROS content and apoptosis rate increased in control fibroblasts and in a glioblastoma cell line by shRNA-mediated silencing of MTRR gene expression . In contrast , wild-type MTRR gene corrected mutant cell lines showed a decrease in ROS and apoptosis levels . To the best of our knowledge , this study provides the first evidence that an impaired remethylation capacity due to low MTRR and MTR activity might be partially responsible for stress response .