Is PrP the road to ruin?

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). In this issue, Resenberger et al (2011) provide evidence for membraneanchored PrP’s role in recognizing a variety of b-sheetrich protein conformers and transducing pro-apoptotic signals. Among various protein-misfolding diseases, Alzheimer’s disease (AD) is characterized by brain plaques composed of the b-amyloid (Ab) peptide and tau. Huntington’s disease is caused by an inherited poly-glutamine expansion in the huntingtin protein, and huntingtin fragments containing these extra residues aggregate and cause neurotoxicity. In Parkinson’s disease, alpha synuclein aggregates into intracellular inclusions called Lewy bodies. During prion diseases, PrP is converted to an abnormal autocatalytic isoform, PrP, which can accumulate in diffuse deposits, amyloid fibrils or plaques. Despite accumulating evidence of the importance of protein misfolding and aggregation in these diseases, the precise mechanisms by which these proteins misfold and trigger neurodegeneration remain unclear. One common feature of these misfolded protein aggregates is their high b-sheet content. PrP is largely a helical and disordered, but, upon conversion to infectious PrP amyloid, becomes predominantly b sheet with bends and turns (Caughey et al, 2009; Smirnovas et al, 2011). Alzheimer’s plaques are composed of high b-sheet Ab fibrils. a-Synuclein exists normally as a natively unfolded protein, but can partially fold into b structures, increasing its propensity for aggregation. The proposed toxic fragment of huntingtin is helical in the native structure, but expanded poly-glutamine sequences can promote the formation of compact b sheet and turn structures. Although large fibrillar and plaque deposits of these misfolded proteins are often the most obvious lesions, the most toxic species appear to be small oligomeric assemblies that may be precursors to larger fibrils (Caughey and Lansbury, 2003) (see Figure 1). The challenge has been not only to define and characterize the toxic oligomeric species but also to determine their neurotoxic mechanisms. Recently, Lauren et al (2009) used Ab oligomers that were formed in vitro and fractionated by size to probe potential cell-surface binding partners. PrP showed high affinity and selectivity in its interaction with Ab oligomers. Moreover, the