PT  - JOURNAL ARTICLE
AU  - Sarah C. Schock
AU  - Jin Xu
AU  - Philippe M. Duquette
AU  - Zhaohong Qin
AU  - Adam J. Lewandowski
AU  - Punarpreet S. Rai
AU  - Charlie S. Thompson
AU  - Erin L. Seifert
AU  - Mary-Ellen Harper
AU  - Hsiao-Huei Chen
TI  - Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor-γ Requires a Novel Essential Cofactor LMO4
AID  - 10.1523/JNEUROSCI.2897-08.2008
DP  - 2008 Nov 19
TA  - The Journal of Neuroscience
PG  - 12433--12444
VI  - 28
IP  - 47
4099  - http://www.jneurosci.org/content/28/47/12433.short
4100  - http://www.jneurosci.org/content/28/47/12433.full
SO  - J. Neurosci.2008 Nov 19; 28
AB  - Activation of peroxisome proliferator-activated receptor-γ (PPARγ) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPARγ signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPARγ agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKIIαCre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPARγ-protective effect. PPARγ signaling activates the promoter of the antioxidant gene SOD2 and this process requires LMO4. Addition of a superoxide dismutase mimetic MnTBAP [manganese(III)tetrakis(4-benzoic acid)porphyrin] bypassed the deficiency in PPARγ signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPARγ and PGC1α (PPARγ coactivator 1α) levels in neurons are elevated by hypoxic stress, and absence of LMO4 impairs their upregulation. Coimmunoprecipitation and mammalian two-hybrid assays revealed that LMO4 interacts in a ligand-dependent manner with PPARγ. LMO4 augments PPARγ-dependent gene activation, in part, by promoting RXRα (retinoid X receptor-α) binding to PPARγ and by increasing PPARγ binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPARγ signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.