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GPI anchoring facilitates propagation and spread of misfolded Sup35 aggregates in mammalian cells
Author(s) -
Speare Jonathan O,
Offerdahl Danielle K,
Hasenkrug Aaron,
Carmody Aaron B,
Baron Gerald S
Publication year - 2010
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2009.392
Subject(s) - biology , microbiology and biotechnology , anchoring , protein folding , evolutionary biology , engineering , structural engineering
Prion diseases differ from other amyloid‐associated protein misfolding diseases (e.g. Alzheimer's) because they are naturally transmitted between individuals and involve spread of protein aggregation between tissues. Factors underlying these features of prion diseases are poorly understood. Of all protein misfolding disorders, only prion diseases involve the misfolding of a glycosylphosphatidylinositol (GPI)‐anchored protein. To test whether GPI anchoring can modulate the propagation and spread of protein aggregates, a GPI‐anchored version of the amyloidogenic yeast protein Sup35NM (Sup35 GPI ) was expressed in neuronal cells. Treatment of cells with Sup35NM fibrils induced the GPI anchor‐dependent formation of self‐propagating, detergent‐insoluble, protease‐resistant, prion‐like aggregates of Sup35 GPI . Live‐cell imaging showed intercellular spread of Sup35 GPI aggregation to involve contact between aggregate‐positive and aggregate‐negative cells and transfer of Sup35 GPI from aggregate‐positive cells. These data demonstrate GPI anchoring facilitates the propagation and spread of protein aggregation and thus may enhance the transmissibility and pathogenesis of prion diseases relative to other protein misfolding diseases.