SELADIN-1/DHCR24 GENE OVEREXPRESSION DECREASES MIGRATION OF IMMATURE IMMORTALIZED NEURONS

DHCR24 (3beta-hydroxysterol delta24-reductase) is a key enzyme to form cholesterol from desmosterol; interestingly, high levels of desmosterol are present during fetal brain development. DHCR24 is also called Seladin-1 (for Selective Alzheimer\u2019s Disease Indicator-1, Sel-1) since it is down-regulated in the brain regions more susceptible to this disease. Moreover, it has been implicated in tumor progression, neuroprotection and oxidative stress, suggesting a prosurvival and antiapoptotic action. In the present study we investigated the expression of Sel-1 in immortalized neurons derived from mature (GT1-7) and immature (GN11) endocrine neurons and a possible role in the neuronal maturation and motility. We found that GT1-7 cells present 100 times higher levels of Sel-1 mRNA and protein compared to GN11 cells as well as a different intracellular distribution. Accordingly, an higher relative amount of desmosterol was present in GN11 cells. In a first series of functional experiments, we found that cyclodextrin-mediated membrane cholesterol/desmosterol substitution did not affect the motility of GN11 cells. By transfection of GN11 cells with a Seladin-1-GFP construct we observed an increase of the cholesterol and a decrease of the desmosterol content, a distribution of the protein similar to mature GT1-7 cells as well as a neurite growth stimulation. Moreover, by microchemotaxis assay, we found that transfected cells showed a decrease of their motility. In conclusions, these results are suggestive of a possible role of Seladin-1/DHCR24 on some event of neuronal development/differentiation, through a control of the intracellular cholesterol/desmosterol ratio