Central to this network are induction of p53 protein expression and strong induction of genes responsible for arresting the cell cycle, as well as a number of p53 regulated pro apoptotic and anti apoptotic genes. p53 is a critical tumor www.selleckchem.com/products/Vandetanib.html suppressor and transcription factor, and it has been linked to cell death in the central nervous system in a number of disorders including most notably neurodegenerative dis orders such as Alzheimers disease and prion diseases. The expression of p53 protein has been found to rap idly increase in neurons in response to a range of insults including DNA damage, oxidative stress, metabolic com promise, and cellular calcium overload. Over expression of PrPC has been shown to enhance staurosporine induced toxicity and activation of caspase 3 in the HEK293 kidney cell line and increase sensitivity Inhibitors,Modulators,Libraries to apoptotic stimuli via p53 dependent pathways in TSM1 neuronal cell line.

Conversely neurons devoid of PrPC expression were reported Inhibitors,Modulators,Libraries to display lower respon Inhibitors,Modulators,Libraries siveness to staurosporine, also via p53 dependent path ways. One of the main pro apoptotic effectors of p53 is BAX, which plays a major role in regulating neuronal death in the brain in response to a number of stimuli. The role of BAX in prion induced neurodegeneration is not well understood. both BAX dependent and BAX inde pendent mechanisms appear to underlie the action of neurotoxic forms of prion proteins.

However, in the muscle of Dox treated Tg mice, only a marginal increase in BAX expression was observed whereas signifi cant over expression of Inhibitors,Modulators,Libraries other p53 regulated pro apoptotic proteins, including BAK1, BBC3 and PMAIP1, and MCL1, were detected, suggesting that PrPC mediated myopathy observed in this model may depend on Bax independent pathways that involve BAK1, BBC3, PMAIP1, and MCL1. We propose a working model to explain the mechanism of PrP mediated myopathy. Dox induced over expression of PrPC in the muscles leads to accumulation of pase 3 activity through a p53 dependent mechanism. Truncation of PrPC occurs between residues 110 and 111 within a region shown to play a pivotal role in its conformational transition to PrPSc. So a better under standing of modulation of this cleavage event and the mechanism for Inhibitors,Modulators,Libraries the truncated PrP fragments as mediators of a toxic cellular response may be very important in dis Mechanism of PrP mediated myopathy the N terminal truncated PrP C1 fragment, which in turn activates p53, thereby inducing p53 regulated pro apop totic networks and myopathic changes.

PrP accumulation has been observed in selleck chem the skeletal mus cles of patients with inclusion body myositis, polymyosi tis, dermatomyositis, and neurogenic muscle atrophy, and we have previously reported that over expression of wild type PrP in the skeletal muscles is sufficient to cause myopathy in the Tg mice and references therein], which suggest that muscular accumulation of PrP may contribute to the pathogenesis of some human muscle diseases.