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Title:   Author  item
                                            KANTHASAMY, ANUMANTHA - IOWA STATE UNIVERSITYitem
                                            CHOI, CHRISTOPHER - IOWA STATE UNIVERSITYitem
                                            Nicholson, Ericitem
                                            ANANTHARAM, VELLAREDDY - IOWA STATE UNIVERSITYitem
                                            Richt, Juergenitem
                                            KANTHASAMY, ARTHI - IOWA STATE UNIVERSITY
  Submitted to: Meeting Abstract
                                    Publication Type: Abstract Only
                                    Publication Acceptance Date: 6/12/2008
                                    Publication  Date: 10/8/2008
                                    Citation: Kanthasamy, A.G., Choi, C., Nicholson, E.M., Anantharam, V., Richt, J.A., Kanthasamy, A. 2008. Divalent Metals Stabilize Cellular Prion Proteins and Alter the Rate of Proteinase-K Dependent Limited Proteolysis [abstract]. Prion 2008. p. 104.Interpretive Summary:
                                Technical Abstract:   Background:  The key biochemical 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.
  Objectives: In the present study, we examined the role of transition metals (Mn**2+ and Cu**2+) on PrP**c expression and degradation in cell culture and brain slice models.
  Methods: Neuronal cells expressing mouse prion proteins with a genetically altered novel epitope (mAb 3F4) and brain slices were exposed to Mn**2+ and Cu**2+ over 24hr. Levels of PrP**c protein and mRNA were measured.  Limited proteolysis, mRNA stability, proteasomal activity and pulse-chase experiments were conducted.
  Results: Metal treatment increased PrP**c levels in both cytosolic and membrane-rich fractions in a time-dependent manner. However, metal treatment neither increased PrP mRNA transcripts nor altered the mRNA stability, indicating that Mn may act at the post-translation and/or degradation levels of PrP**c. Additionally, metal exposure did not alter the proteasomal or lysosomal degradation pathway. Pulse-chase analysis showed that the PrP**c turnover rate was significantly decreased with metal treatment.  Limited digestion with PK also revealed that metal treatment decreased the digestion rate of PrP**c.
  Discussion: Collectively, these data suggest that certain divalent metals can alter the normal processing of PrP**c, resulting in the accumulation of PrP**c with altered susceptibility to PK.


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