Abstract
BackgroundWe have reported that doxycycline-induced over-expression of wild type prion protein (PrP) in skeletal muscles of Tg(HQK) mice is sufficient to cause a primary myopathy with no signs of peripheral neuropathy. The preferential accumulation of the truncated PrP C1 fragment was closely correlated with these myopathic changes. In this study we use gene expression profiling to explore the temporal program of molecular changes underlying the PrP-mediated myopathy.ResultsWe used DNA microarrays, and confirmatory real-time PCR and Western blot analysis to demonstrate deregulation of a large number of genes in the course of the progressive myopathy in the skeletal muscles of doxycycline-treated Tg(HQK) mice. These include the down-regulation of genes coding for the myofibrillar proteins and transcription factor MEF2c, and up-regulation of genes for lysosomal proteins that is concomitant with increased lysosomal activity in the skeletal muscles. Significantly, there was prominent up-regulation of p53 and p53-regulated genes involved in cell cycle arrest and promotion of apoptosis that paralleled the initiation and progression of the muscle pathology.ConclusionThe data provides the first in vivo evidence that directly links p53 to a wild type PrP-mediated disease. It is evident that several mechanistic features contribute to the myopathy observed in PrP over-expressing mice and that p53-related apoptotic pathways appear to play a major role.
Highlights
We have reported that doxycycline-induced over-expression of wild type prion protein (PrP) in skeletal muscles of Tg(HQK) mice is sufficient to cause a primary myopathy with no signs of peripheral neuropathy
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 cytoplasmic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder [7]
Induction of PrPC in the Skeletal Muscle of Transgenic Mice Results in a Temporally Regulated Transcriptional Profile The transgenic mice [Tg(HQK)] used in this study have been described previously, in which PrPC is exclusively expressed in skeletal muscles under the strict control of doxycycline (Dox) and the induced over-expression of PrPC leads to a progressive primary myopathy [7]
Summary
We have reported that doxycycline-induced over-expression of wild type prion protein (PrP) in skeletal muscles of Tg(HQK) mice is sufficient to cause a primary myopathy with no signs of peripheral neuropathy. In this study we use gene expression profiling to explore the temporal program of molecular changes underlying the PrP-mediated myopathy. Cellular prion protein (PrPC) is a ubiquitous glycosylphosphatidyl-inositol (GPI) anchored glycoprotein that has gained enormous attention as the central factor in prion diseases [1]. In these diseases PrPC is converted through conformational change to a pathological form (page number not for citation purposes). Over-expression of PrPC has been shown to exert a protective effect in BAX and TNF -mediated cell death and a pro-apoptotic function in studies of staurosporine-induced cell death [3,4,5]. It has been demonstrated that depletion of endogenous PrP reduces susceptibility to staurosporine-induced caspase 3 and p53 activation [6]
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