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Mutant prion protein‐mediated aggregation of normal prion protein in the endoplasmic reticulum: implications for prion propagation and neurotoxicity
Author(s) -
Gu Yaping,
Verghese Susamma,
Mishra Ravi Shankar,
Xu Xeumin,
Shi Yongchang,
Singh Neena
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01255.x
Subject(s) - endoplasmic reticulum , mutant , green fluorescent protein , biology , gene isoform , scrapie , microbiology and biotechnology , prion protein , mutant protein , transmembrane protein , gene , genetics , medicine , receptor , disease , pathology
Familial prion disorders are believed to result from spontaneous conversion of mutant prion protein (PrP M ) to the pathogenic isoform (PrP Sc ). While most familial cases are heterozygous and thus express the normal (PrP C ) and mutant alleles of PrP, the role of PrP C in the pathogenic process is unclear. Plaques from affected cases reveal a heterogeneous picture; in some cases only PrP M is detected, whereas in others both PrP C and PrP M are transformed to PrP Sc . To understand if the coaggregation of PrP C is governed by PrP mutations or is a consequence of the cellular compartment of PrP M aggregation, we coexpressed PrP M and PrP C in neuroblastoma cells, the latter tagged with green fluorescent protein (PrP C–GFP ) for differentiation. Two PrP M forms (PrP 231T , PrP 217R/231T ) that aggregate spontaneously in the endoplasmic reticulum (ER) were generated for this analysis. We report that PrP C–GFP aggregates when coexpressed with PrP 231T or PrP 217R/231T , regardless of sequence homology between the interacting forms. Furthermore, intracellular aggregates of PrP 231T induce the accumulation of a C‐terminal fragment of PrP, most likely derived from a potentially neurotoxic transmembrane form of PrP ( Ctm PrP) in the ER. These findings have implications for prion pathogenesis in familial prion disorders, especially in cases where transport of PrP M from the ER is blocked by the cellular quality control.