A Common Mechanism of Proteasome Impairment by Neurodegenerative Disease‐Associated Oligomers

Neurodegenerative diseases are characterized by an accumulation of misfolded proteins, loss of proteostasis, and the progressive death of neurons. It is well established that the ubiquitin proteasome system (UPS), a major regulator of proteostasis, is impaired in essentially all neurodegenerative diseases. Accordingly, targeted proteasome inhibition in the brain recapitulates many physiological and behavioral hallmarks of neurodegeneration. Several studies have attempted to investigate how the UPS is impaired by protein aggregation, but none of these models provide detailed mechanisms of impairment nor can they be applied to the general spectrum of neurodegenerative diseases. Here, we show that three proteins implicated in Alzheimer's, Parkinson's, and Huntington's diseases form soluble oligomers sharing a similar structure that potently inhibits the proteasome with low nanomolar affinity. These oligomers bind to the 20S proteasome core particle and prevent opening of the substrate‐entry channel, thereby impairing both ubiquitin dependent and independent protein degradation. Mechanistic analysis demonstrates that these oligomers allosterically block a well characterized conformational change in the α‐subunits that is required for substrate entry into the catalytic chamber of the 20S proteasome. Proteasome impairment by these oligomers is expected to accelerate further protein accumulation in a positive feedback loop, thereby contributing to the onset and progression of disease. Our findings suggest that proteasome impairment in many neurodegenerative diseases may have a common mechanism, and identify an excellent target for future drug discovery efforts. Support or Funding Information This work was supported by start‐up funds to DMS from West Virginia University and by NIH‐R01GM107129 to DMS.