Aggregation of cellular prion protein is initiated by proximity-induced dimerization

Abstract

Prion diseases or transmissible spongiform encephalopathies (TSEs) are infectious and fatal neurodegenerative disorders in humans and animals. Pathological features of TSEs include the conversion of cellular prion protein (PrPC) into an altered disease-associated conformation generally designated PrPSc, abnormal deposition of PrPSc aggregates, and spongiform degeneration of the brain. The molecular steps leading to PrPC aggregation are unknown. Here, we have utilized an inducible oligomerization strategy to test if, in the absence of any infectious prion particles, the encounter between PrPC molecules may trigger its aggregation in neuronal cells. A chimeric PrPC composed of one (Fv1) or two (Fv2) modified FK506-binding protein (Fv) fused with PrPC were created, and transfected in N2a cells. Similar to PrPC, Fv1-PrP and Fv2-PrP were glycosylated, displayed normal localization, and anti-apoptotic function. When cells were treated with the dimeric Fv ligand AP20187, to induce dimerization (Fv1) or oligomerization (Fv2) of PrPC, both dimerization and oligomerization of PrPC resulted in the de novo production, release and deposition of extracellular PrP aggregates. Aggregates were insoluble in non-ionic detergents and partially resistant to proteinase K. These findings demonstrate that homologous interactions between PrPC molecules may constitute a minimal and sufficient molecular event leading to PrPC aggregation and extracellular deposition. © 2007 The Authors.