Proteasome activation is a mechanism for pyrazolone small molecules displaying therapeutic potential in amyotrophic lateral sclerosis

Paul C. Trippier, Kevin Tianmeng Zhao, Susan G. Fox, Isaac T. Schiefer, Radhia Benmohamed, Jason Moran, Donald R. Kirsch, Richard I. Morimoto, Richard B. Silverman

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

(Chemical Equation Presented) Amyotrophic lateral sclerosis (ALS) is a progressive and ultimately fatal neurodegenerative disease. Pyrazolone containing small molecules have shown significant disease attenuating efficacy in cellular and murine models of ALS. Pyrazolone based affinity probes were synthesized to identify high affi nity binding partners and ascertain a potential biological mode of action. Probes were confirmed to be neuroprotective in PC12-SOD1G93A cells. PC12-SOD1G93A cell lysates were used for protein pull-down, affinity purification, and subsequent proteomic analysis using LC-MS/MS. Proteomics identified the 26S proteasome regulatory subunit 4 (PSMC1), 26S proteasome regulatory subunit 6B (PSMC4), and T-complex protein 1 (TCP-1) as putative protein targets. Coincubation with appropriate competitors confirmed the authenticity of the proteomics results. Activation of the proteasome by pyrazolones was demonstrated in the absence of exogenous proteasome inhibitor and by restoration of cellular protein degradation of a fluorogenic proteasome substrate in PC12-SOD1G93A cells. Importantly, supplementary studies indicated that these molecules do not induce a heat shock response. We propose that pyrazolones represent a rare class of molecules that enhance proteasomal activation in the absence of a heat shock response and may have therapeutic potential in ALS.

Original languageEnglish (US)
Pages (from-to)823-829
Number of pages7
JournalACS Chemical Neuroscience
Volume5
Issue number9
DOIs
StatePublished - Sep 17 2014

Keywords

  • Amyotrophic lateral sclerosis
  • Drug discovery
  • Neurodegeneration
  • Proteasome activator
  • Pyrazolone
  • Target identification

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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  • Cite this

    Trippier, P. C., Zhao, K. T., Fox, S. G., Schiefer, I. T., Benmohamed, R., Moran, J., Kirsch, D. R., Morimoto, R. I., & Silverman, R. B. (2014). Proteasome activation is a mechanism for pyrazolone small molecules displaying therapeutic potential in amyotrophic lateral sclerosis. ACS Chemical Neuroscience, 5(9), 823-829. https://doi.org/10.1021/cn500147v