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A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers

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  • Tiffany A. Thibaudeau

    (West Virginia University, School of Medicine, Department of Biochemistry)

  • Raymond T. Anderson

    (West Virginia University, School of Medicine, Department of Biochemistry)

  • David M. Smith

    (West Virginia University, School of Medicine, Department of Biochemistry)

Abstract

Protein accumulation and aggregation with a concomitant loss of proteostasis often contribute to neurodegenerative diseases, and the ubiquitin–proteasome system plays a major role in protein degradation and proteostasis. Here, we show that three different proteins from Alzheimer’s, Parkinson’s, and Huntington’s disease that misfold and oligomerize into a shared three-dimensional structure potently impair the proteasome. This study indicates that the shared conformation allows these oligomers to bind and inhibit the proteasome with low nanomolar affinity, impairing ubiquitin-dependent and ubiquitin-independent proteasome function in brain lysates. Detailed mechanistic analysis demonstrates that these oligomers inhibit the 20S proteasome through allosteric impairment of the substrate gate in the 20S core particle, preventing the 19S regulatory particle from injecting substrates into the degradation chamber. These results provide a novel molecular model for oligomer-driven impairment of proteasome function that is relevant to a variety of neurodegenerative diseases, irrespective of the specific misfolded protein that is involved.

Suggested Citation

  • Tiffany A. Thibaudeau & Raymond T. Anderson & David M. Smith, 2018. "A common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03509-0
    DOI: 10.1038/s41467-018-03509-0
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    Cited by:

    1. Chang Hoon Ji & Hee Yeon Kim & Min Ju Lee & Ah Jung Heo & Daniel Youngjae Park & Sungsu Lim & Seulgi Shin & Srinivasrao Ganipisetti & Woo Seung Yang & Chang An Jung & Kun Young Kim & Eun Hye Jeong & S, 2022. "The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Kwadwo A. Opoku-Nsiah & Andres H. Pena & Sarah K. Williams & Nikita Chopra & Andrej Sali & Gabriel C. Lander & Jason E. Gestwicki, 2022. "The YΦ motif defines the structure-activity relationships of human 20S proteasome activators," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Daniel C. Carrettiero & Maria C. Almeida & Andrew P. Longhini & Jennifer N. Rauch & Dasol Han & Xuemei Zhang & Saeed Najafi & Jason E. Gestwicki & Kenneth S. Kosik, 2022. "Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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