The regulation of catalase activity by PPAR γ is affected by α-synuclein

Objective: While evidence for oxidative injury is frequently detected in brains of humans affected by Parkinson's disease (PD) and in relevant animal models, there is uncertainty regarding its cause. We tested the potential role of catalase in the oxidative injury that characterizes PD. Methods: Utilizing brains of A53T alpha-Syn and ntg mice, and cultured cells, we analyzed catalase activity and expression, and performed biochemical analyses of peroxisomal metabolites. Results: Lower catalase expression and lower activity levels were detected in A53T alpha-Syn brains and alpha-Syn-expressing cells. The effect on catalase activity was independent of disease progression, represented by mouse age and alpha-Syn mutation, suggesting a potential physiological function for alpha-Syn. Notably, catalase activity and expression were unaffected in brains of mice modeling Alzheimer's disease. Moreover, we found that alpha-Syn expression downregulate the peroxisome proliferator-activated receptor (PPAR)gamma, which controls catalase transcription. Importantly, activation of either PPAR gamma 2, PPAR alpha or retinoic X receptor eliminated the inhibiting effect of alpha-Syn on catalase activity. In addition, activation of these nuclear receptors enhanced the accumulation of soluble alpha-Syn oligomers, resulting in a positive association between the degree of soluble alpha-Syn oligomers and catalase activity. Of note, a comprehensive biochemical analysis of specific peroxisomal metabolites indicated no signs of dysfunction in specific peroxisomal activities in brains of A53T alpha-Syn mice. Interpretation: Our results suggest that alpha-Syn expression may interfere with the complex and overlapping network of nuclear receptors transcription activation. In result, catalase activity is affected through mechanisms involved in the regulation of soluble alpha-Syn oligomers.