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Small Molecule Modulation of Proteasome Assembly

Evert Njomen1, Pawel A Osmulski2, Corey L Jones1

  • 1Department of Chemistry , Michigan State University , East Lansing , Michigan 48824 , United States.

Biochemistry
|June 14, 2018
PubMed

Insights

A novel small molecule, TCH-165, enhances proteasome activity to degrade disease-linked intrinsically disordered proteins (IDPs). This discovery offers new therapeutic avenues for neurodegenerative diseases and cancers by targeting protein aggregation.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Proteostasis

Background:

  • The 20S proteasome is crucial for degrading intrinsically disordered proteins (IDPs).
  • Accumulation of IDPs, due to mutations, stress, or aging, is linked to cancer and neurodegenerative diseases.
  • Targeting 20S-mediated proteolysis presents therapeutic opportunities.

Purpose of the Study:

  • To investigate the effect of the small molecule TCH-165 on proteasome assembly and function.
  • To determine if TCH-165 can enhance the degradation of disease-associated IDPs.
  • To explore the mechanism by which TCH-165 modulates proteasome complexes.

Main Methods:

  • Treatment with the small molecule TCH-165.
  • Analysis of proteasome complex levels and assembly.
  • Assessment of proteolysis rates for various proteins, including IDPs and structured proteins.
  • Evaluation of ubiquitinated protein clearance under different proteasome capping conditions.

Main Results:

  • TCH-165 treatment increased the levels of the free 20S proteasome core particle.
  • Enhanced proteolysis of IDPs such as alpha-synuclein, tau, ornithine decarboxylase, and c-Fos was observed.
  • Degradation of structured proteins remained unaffected.
  • Ubiquitinated protein clearance was maintained by singly capped proteasomes but impaired upon complete 19S cap depletion.

Conclusions:

  • TCH-165 modulates proteasome assembly, increasing free 20S levels and enhancing IDP degradation.
  • This represents the first small molecule shown to target disordered proteins for degradation by regulating proteasome complex dynamics.
  • The findings suggest TCH-165 as a potential therapeutic agent for diseases characterized by IDP accumulation.

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