Prion diseases comprise a family of fatal
neurodegenerative disorders caused by the conformational re-arrangement of a normal host-encoded
protein, PrP (C) , to an abnormal infectious
isoform termed PrP (Sc) . Currently, the precise cellular mechanism(s) underlying
prion disease pathogenesis remain unclear. Evidence suggests a role for the
ubiquitin proteasome system (UPS), a protein degradation pathway that is critical for maintaining cellular proteostasis. Dysfunction of the UPS has been implicated in various
neurodegenerative diseases. However, the mechanisms of this impairment remain unknown in many cases, and evidence that disease-associated misfolded
proteins are able to directly inhibit the function of the
proteasome has been lacking. Recently, we have shown data describing a mechanism of
proteasome impairment by the direct interaction of β-sheet-rich PrP to reduce gate opening and inhibit substrate entry. This novel mechanism may provide a model for how other misfolded, disease-associated
proteins might interact with the
proteasome to disrupt its function. Targeting the UPS to restore proteostasis in
neurodegenerative disorders in which misfolded
proteins accumulate offers a possible target for therapeutic intervention.