LOW EXPRESSION OF SELADIN-1/DHCR24 GENE CONFERS RESISTANCE TO TOXIC INSULTS IN IMMATURE GnRH NEURONS

Cholesterol is essential for the correct development of the central nervous system. Recently, a new gene termed "SELective Alzheimer's Disease INdicator 1" (Seladin-1, sel-1) was characterized as coding for a cholesterol-biosynthetic enzyme 3beta-hydroxysterol delta24-reductase (DHCR24), whose mutations lead to tissue cholesterol depletion, and desmosterol accumulation. Moreover, it has been proposed that sel-1 gene product may exert prosurvival and antiapoptotic actions. Surprisingly, sel-1 null mice are viable but infertile, possibly due to a lack of sex steroids. However, the assessed actions of sel-1 on neuronal function lead to hypothesize a role also in the development/function of GnRH neurons. Cell lines of mature (GT1-7) and immature (GN11) GnRH neurons were then used for in vitro experiments. In previous experiments we found that GT1-7 cells present 100 times higher expression of sel-1 compared to GN11 cells. Nevertheless, no difference were observed between the two cell lines in term of Sel-1 immunoreactivity, distributed around the nucleus associated by endoplasmic reticulum, and of proliferation rate after removal of exogenous cholesterol. However the total sterol content in the absence of exogenous cholesterol was higher in GT1-7 cells and a different accumulation of free cholesterol, detected by filipin staining, was also observed. GT1-7 cells have been found to be more sensitive to desmosterol and cholesterol toxicity and to induction of oxidative stress. Finally, the oxidative stress-induced decrease of sel-1 expression was significantly more evident in GT1-7 than GN11 cells. In conclusion, these data suggest that a) mature and immature GnRH neurons have a differential cholesterol synthesis/metabolism, b) immature GN11 neurons utilize part of the exogenous cholesterol; c) the possible major fraction of desmosterol in GN11 cells make them more resistant to toxic insults and d) the lower levels of sel-1 in immature GnRH cells may suggest a possible role as a mediator of toxic insult response in these neurons. Further studies are needed to determine the exact roles of desmosterol and sel-1 in the development of GnRH neuronal. (Grants: PRIN2005 # 2005051740)