Open AccessCell-Specific Metabolism and Pathogenesis of Transmembrane Prion Protein
Author(s) -
Yixuan Gu,
Xiaohua Luo,
Subhabrata Basu,
Hisashi Fujioka,
Neena Singh
Publication year - 2006
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.26.7.2697-2715.2006
Subject(s) - biology , biogenesis , microbiology and biotechnology , transmembrane protein , cytokinesis , endoplasmic reticulum , downregulation and upregulation , neurodegeneration , amino acid , cell , cell division , biochemistry , disease , receptor , medicine , pathology , gene
The C-transmembrane form of prion protein (Ctm PrP) has been implicated in prion disease pathogenesis, but the factors underlying its biogenesis and cyotoxic potential remain unclear. Here we show thatCtm PrP interferes with cytokinesis in cell lines where it is transported to the plasma membrane. These cells fail to separate following cell division, assume a variety of shapes and sizes, and contain multiple nuclei, some of which are pyknotic. Furthermore, the synthesis and transport ofCtm PrP to the plasma membrane are modulated through a complex interaction betweencis - andtrans -acting factors and the endoplasmic reticulum translocation machinery. Thus, insertion of eight amino acids before or within the N region of the N signal peptide (N-SP) of PrP results in the exclusive synthesis ofCtm PrP regardless of the charge conferred to the N region. Subsequent processing and transport ofCtm PrP are modulated by specific amino acids in the N region of the N-SP and by the cell line of expression. Although the trigger forCtm PrP upregulation in naturally occurring prion disorders remains elusive, these data highlight the underlying mechanisms ofCtm PrP biogenesis and neurotoxicity and reinforce the idea thatCtm PrP may serve as the proximate cause of neuronal death in certain prion disorders.