Is PrP the road to ruin?

Abstract

EMBO J 30 10, 2057–2070 (2011); published online March 25 2011

Neurodegenerative disorders are one among the most debilitating diseases of an ageing population. Understanding the mechanisms of neuronal cell death during pathogenesis of diseases such as Alzheimer's, Parkinson's, Huntington's, and prion diseases is key to addressing the options for treatment and prevention of brain deterioration. One feature of many such diseases is the accumulation of specific misfolded proteins. Often these misfolded proteins take the form of large amyloid fibrils or plaques, but recent observations implicate small soluble oligomers as the primary causes of neuronal dysfunction. How these misfolded proteins trigger cell death pathways is largely unknown, but some reports have suggested mediation by normal cellular prion protein (PrP^C). In this issue, Resenberger et al (2011) provide evidence for membrane-anchored PrP^C's role in recognizing a variety of β-sheet-rich protein conformers and transducing pro-apoptotic signals.

Figure 1

Schematic of proposed role of PrP in pro-apoptotic signalling during neurodegenerative diseases. Native proteins exist in equilibrium with partially or completely unfolded forms. In some instances, partially misfolded proteins can adopt β structures with the propensity to aggregate and form amyloid fibrils. However, along the pathway to fibril formation, the smaller β oligomers mediate toxic effects. PrP^C is one of the potentially multiple cell-surface receptors capable of binding to the toxic oligomers and mediating pro-apoptotic signals in conjunction with other molecules.