Over expression of PrPC has been shown to exert a protective effect in BAX and TNF medi ated cell death and conversely a pro apoptotic function in studies of staurosporine induced cell death. It has also been demonstrated that depletion of endogenous PrP reduces susceptibility to staurosporine induced caspase 3 and p53 activation. In a previous www.selleckchem.com/products/Gefitinib.html study we generated transgenic mice, Tg, that express human PrPC exclusively in the skel etal muscles under tight regulation by doxycycline. We found that induced over expression of PrPC in the muscles leads to a progressive primary myopathy characterized by increased variation of myofiber size, centrally located nuclei and endomysial fibrosis, in the absence of cytoplas mic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder.

While the pathogenic mecha nism of the PrP mediated myopathy was not determined, an interesting observation was that the myopathy was accompanied by preferential accumulation Inhibitors,Modulators,Libraries of an N termi nal truncated PrPC fragment, Inhibitors,Modulators,Libraries which was confirmed to be the C1 fragment resulting from normal PrPC process ing. The C1 fragment is also found in the skeletal muscles of wild type mouse, but at a much lower level and a molar ratio of close to 1 1 over full length PrPC, in contrast to a ratio of 3 1 in the Dox induced Tg model. A number of studies have shown the expression Inhibitors,Modulators,Libraries of N ter minus truncated forms of PrPC to be associated with tox icity in animal models. The protein Doppel, which is homologous to the C terminus of PrP, has also been shown to be cytotoxic when ectopically expressed in neurons.

In both cases, the toxicity can be abro gated by the co expression Inhibitors,Modulators,Libraries of full length PrPC. The C1 fragment has also been reported to potentiate stau rosporine induced toxicity via caspase 3 activation in cul tured cells, but this toxic effect is similar to what was reported for full length PrPC. We hypothesize that the high levels of the C1 fragment that accumulate in Dox treated Tg mice is largely responsible for the toxic effect that leads to the development of myopathy in these mice. In order to understand the molecular mecha nism that underlies this PrP toxicity, we have performed microarray analysis to determine gene regulatory net works that are triggered following overexpression of PrPC Inhibitors,Modulators,Libraries in mainly the skeletal muscles of Tg mice. Methods Animals and Treatment The doxycycline inducible Tg mice were described previously. The HQK transgene contained two genes reverse tetracycline responsive transcription activator under the control of the mouse PrP promoter of the half genomic PrP clone, and human PrP ORF regulated by the tetracycline responsive promoter from the core plasmid.