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Bruce A Pfeffer; Libin Xu; Steven J Fliesler

Oxysterol-induced expression of genes associated with autism and allied pathways in 661W cells

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Purpose : Smith-Lemli-Opitz syndrome (SLOS), caused by mutations in the gene for 7-dehydrocholesterol reductase, catalyzes the last step in cholesterol (CHOL) synthesis. Oxysterols derived from the CHOL precursor 7-dehydroCHOL accumulate in tissues of affected individuals, and are toxic to photoreceptors in our non-genetic rat model of SLOS. We previously reported results from a gene array performed on 661W cells (a mouse cone-derived cell line) treated with a SLOS-specific oxysterol (EPCD), as well as with 7-ketoCHOL, showing that loss of viability was associated with differentially expressed genes (DEG) involving CHOL synthesis, ER/oxidative stress, DNA damage, and autophagy pathways. Here, we further mined the array data for enrichment related to CHOL efflux, iron and heme metabolism, synapses, circadian clock, and autism spectrum disorder (ASD), a neurological defect found in SLOS patients.

Methods : As previously described, 661W cultures were incubated (n=3) with either oxysterols, CHOL, or vehicle control (VC). RNA samples were harvested prior to global loss of viability. After conversion of raw data, mean fold changes (FC) vs. VC, and adjusted P-values (aP) were computed; thresholds for DEG were FC ≥ 1.5 and aP ≤ 0.001. Enrichment analysis utilized LRpath.


Results : ABCA1 was significantly upregulated by treatment with EPCD and 7-ketoCHOL, but not CHOL. Along with elevated expression of HMOX1, oxysterols induced DEG for heme synthesis and its regulation, bilirubin and iron cycling, and ferroptosis. The EPCD DEG set showed enrichment of genes related to synaptic structure and function (P<10E-6; almost all down-regulated), with 40/120 among the top 2500 ASD candidates from a gene interaction network ( Annotations for ASD-associated processes from EPCD-treated samples also indicated dysregulation (P<0.05) of: cell junctions, cell-matrix adhesion, methyltransferase activity, and signaling via wnt, kinases, and growth factors. Upstream and downstream effectors for “ASD genes” RELN, FMR1, and MECP2 were also affected. Both oxysterols (and CHOL to a lesser extent) dysregulated numerous DEG for clock function, including CLOCK, RORA, and NR1D2.

Conclusions : Using disease-specific metabolites exogenously applied to an otherwise unaffected photoreceptor cell line, we show that this in vitro model of SLOS may be exploited to further elucidate the molecular basis for neurological disease.


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