NR AREN
AU Kiachopoulos,S.; Heske,J.; Tatzelt,J.; Winklhofer,K.F.
TI Misfolding of the prion protein in the secretory pathway and at the plasma membrane; implications for prion diseases
QU TSE-Forum, 4. Kongress - Nationale TSE-Forschungsplattform, Düsseldorf 28.10.-29.10.2004, Poster GL-22
PT Konferenz-Poster
AB
A key feature in prion diseases is the conversion of the cellular prion protein PrPc to the pathological isoform PrPsc. We recently found that suramin, a bis-hexasulfonated naphthylurea derivative which has been used for the treatment of African sleeping sickness, depletes PrPc from the plasma membrane. As a consequence, PrPsc propagation was inhibited in Scrapie-infected N2a (ScN2A) cells and the onset of prion disease was significantly delayed in scrapie-infected mice (Gilch et al., 2001). A mechanistic analysis of this effect revealed that suramin-induced misfolding occurs at the plasma membrane and is dependent on the proximal region of the C-terminal domain (aa 90-158) of PrPc. The conformational transition induces rapid internalization, mediated by the unstructured N-terminal domain and subsequent intracellular degradation of PrPc. Consequently, PrPdeltaN adopts a misfolded conformation at the plasma membrane; however, internalization is significantly delayed. We also found that misfolding and intracellular retention of PrPc can be induced by copper, moreover, copper interferes with the propagation of the pathogenic prion protein (PrPsc) in ScN2a cells. Our study revealed a quality control pathway for aberrant PrP conformers present at the plasma membrane and identified distinct PrP domains involved.
References:
Gilch et al., EMBO J, 20, 3957-3966 (2001)
Kiachopoulos et al., Traffic, 5, 426-436 (2004)
AD Sophia Kiachopoulos, Johanna Heske, Jorg Tatzelt and Konstanze F. Winklhofer, Max-Planck-Institut für Biochemie, Am Klopferspitz 18, Martinsried
SP englisch
PO Deutschland
OR Tagungsband