Peroxisome proliferator-activated receptor γ is inhibited by histone deacetylase 4 in cortical neurons under oxidative stress

Peroxisome proliferator-activated receptor gamma (PPAR gamma) serves an essential protective function in neurons. Although PPAR gamma activation is known to reduce brain tissue damage in distinct models of brain diseases, the regulation of PPAR gamma activity in neurons is unclear. Here, we report that histone deacetylase 4 (HDAC4) mediates PPAR gamma inhibition in cultured cortical neurons under oxidative stress. Our data indicate that HDAC4 physically interacts with PPAR gamma and represses PPAR gamma transcription activity in cultured cortical neurons. Upon H2O2 treatment, HDAC4 translocates from the cytoplasm to the nucleus, where it inhibits PPAR gamma transcription. This inhibition rendered neurons more vulnerable to H2O2 insult. In contrast, knockdown of HDAC4 by introduction of a specific microRNA abolishes the oxidative stress-induced repression of PPAR gamma in neurons and also reduces the number of dead neurons induced by H2O2. Furthermore, over-expression of PPAR gamma protects neurons from either HDAC4 over-expression-or H2O2-induced damage. These data suggest that HDAC4 works to repress PPAR gamma transcription and regulates neuronal death by inhibiting PPAR gamma pro-survival activity.