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The Journal of Neuroscience, November 19, 2008, 28(47):12433-12444; doi:10.1523/JNEUROSCI.2897-08.2008

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Neurobiology of Disease
Rescue of Neurons from Ischemic Injury by Peroxisome Proliferator-Activated Receptor- Requires a Novel Essential Cofactor LMO4

Sarah C. Schock,^1 * Jin Xu,^1 * Philippe M. Duquette,¹ Zhaohong Qin,¹ Adam J. Lewandowski,¹ Punarpreet S. Rai,¹ Charlie S. Thompson,¹ Erin L. Seifert,² Mary-Ellen Harper,² and Hsiao-Huei Chen^1,3

¹Ottawa Health Research Institute, Neuroscience, ²Department of Biochemistry, Microbiology and Immunology, and ³Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada K1H 8M5

Correspondence should be addressed to Hsiao-Huei Chen, Ottawa Health Research Institute, Neuroscience, 451 Smyth Road, Room 2422, Ottawa, Ontario, Canada K1H 8M5. Email: hchen{at}uottawa.ca

Activation of peroxisome proliferator-activated receptor- (PPAR) 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 PPAR signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPAR agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKIICre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain. Expressing LMO4 in LMO4-null cortical neurons rescued the PPAR-protective effect. PPAR 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 PPAR signaling and was able to directly rescue LMO4-null cortical neurons from ischemic injury. Like LMO4, PPAR and PGC1 (PPAR coactivator 1) 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 PPAR. LMO4 augments PPAR-dependent gene activation, in part, by promoting RXR (retinoid X receptor-) binding to PPAR and by increasing PPAR binding to its target DNA sequence. Together, our results identify LMO4 as an essential hypoxia-inducible cofactor required for PPAR signaling in neurons. Thus, upregulation of LMO4 expression after stroke is likely to be an important determinant of neuron survival.

Key words: LMO4; PPAR; stroke; excitotoxicity; hypoxia; SOD2

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Received June 24, 2008; revised Sept. 18, 2008; accepted Oct. 8, 2008.

Correspondence should be addressed to Hsiao-Huei Chen, Ottawa Health Research Institute, Neuroscience, 451 Smyth Road, Room 2422, Ottawa, Ontario, Canada K1H 8M5. Email: hchen{at}uottawa.ca

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