PRNP and Alzheimer disease: For example, aggregated β-sheet-rich PrP blocks the opening of the 20S proteasome particle, leading to reduced proteasomal activity.58 Ubiquitinated and aggregated tau in AD can block the gate of the 19S catalytic particle by binding to its recognition site, leading to a traffic jam and impaired proteasomal degradation.30, 32 In addition, recent studies have shown that aggregates of many other pathogenic proteins in neurodegenerative disorders can directly inhibit proteasome activity.59, 60, 61, 62