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Title:   Author  item
                                            CHOI, CHRISTOPHER - IOWA STATE UNIVERSITYitem
                                            ANANTHARAM, VELLAREDDY - IOWA STATE UNIVERSITYitem
                                            Nicholson, Ericitem
                                            Richt, Juergenitem
                                            KANTHASAMY, ARTHI - IOWA STATE UNIVERSITYitem
                                            KANTHASAMY, ANUMANTHA - IOWA STATE UNIVERSITY
  Submitted to: Society for Neuroscience Abstracts and Proceedings
                                    Publication Type: Abstract Only
                                    Publication Acceptance Date: 8/15/2006
                                    Publication  Date: 10/14/2006
                                    Citation: Choi, C.J., Anantharam, V., Nicholson, E., Richt, J., Kanthasamy, A., Kanthasamy, A.G. 2006. Manganese upregulates cellular prion proteins and inhibits the rate of proteinase-K dependent limited proteolysis in neuronal cells [abstract]. Society for Neuroscience. Paper No. 74.23.Interpretive Summary:
                                Technical Abstract: The key event in the pathogenesis of prion diseases is the conversion of normal cellular prion proteins (PrP**c) to the proteinase K (PK) resistant, abnormal form (PrP**sc); however, the cellular mechanisms underlying the conversion remain enigmatic.  Binding of divalent cations such as copper to the octapeptide repeat regions of PrP has been shown to be important for the stability of the protein. Nevertheless, the roles of other divalent cations in the normal processing of cellular PrP**c are not well understood.  In the present study, we examined the effect of manganese (Mn) on PrP**c expression and degradation in neuronal cells expressing mouse prion proteins with a genetically altered novel epitope (mAb 3F4).  Exposure of Mn (100μM) over the course of 24 hr increased PrP levels in both cytosolic and membrane-rich fractions in a time-dependent manner.  Interestingly, Mn treatment neither increased PrP mRNA transcripts as measured by qRT-PCR nor altered the mRNA stability as determined in Actinomycin D treated cells, indicating that the effect of Mn may be at the level of post-translation and/or degradation levels of PrP.   In order to determine whether the accumulation of PrP is due to impairment of the proteasomal degradation pathway by Mn, proteasomal activity and ubiquitination were measured.  The results showed no significant alteration of the proteasomal degradation pathway.  Notably, pulse-chase analysis showed that the PrP**c turnover rate is significantly decreased with manganese treatment.  Furthermore, limited digestion with PK also revealed that manganese treatment decreased the digestion rate of the PrP.  These data together clearly suggest that the divalent metal manganese can alter the normal processing of PrP, resulting in the accumulation of PrP with altered susceptibility to PK.


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