Sulforaphane enhances proteasomal and autophagic activities in mice and is a potential therapeutic reagent for Huntington's disease

Yanying Liu, Casey L. Hettinger, Dong Zhang, Khosrow Rezvani, Xuejun Wang, Hongmin Wang

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

The ubiquitin proteasome system (UPS) is impaired in Huntington's disease, a devastating neurodegenerative disorder. Sulforaphane, a naturally occurring compound, has been shown to stimulate UPS activity in cell cultures. To test whether sulforaphane enhances UPS function in vivo, we treated UPS function reporter mice ubiquitously expressing the green fluorescence protein (GFP) fused to a constitutive degradation signal that promotes its rapid degradation in the conditions of a healthy UPS. The modified GFP is termed GFP UPS reporter (GFPu). We found that both GFPu and ubiquitinated protein levels were significantly reduced and the three peptidase activities of the proteasome were increased in the brain and peripheral tissues of the mice. Interestingly, sulforaphane treatment also enhanced autophagy activity in the brain and the liver. To further examine whether sulforaphane promotes mutant huntingtin (mHtt) degradation, we treated Huntington's disease cells with sulforaphane and found that sulforaphane not only enhanced mHtt degradation but also reduced mHtt cytotoxicity. Sulforaphane-mediated mHtt degradation was mainly through the UPS pathway as the presence of a proteasome inhibitor abolished this effect. Taken together, these data indicate that sulforaphane activates protein degradation machineries in both the brain and peripheral tissues and may be a therapeutic reagent for Huntington's disease and other intractable disorders.

Original languageEnglish (US)
Pages (from-to)539-547
Number of pages9
JournalJournal of Neurochemistry
Volume129
Issue number3
DOIs
StatePublished - May 2014

Keywords

  • autophagy
  • mutant huntingtin
  • neurodegeneration
  • protein degradation
  • sulforaphane
  • ubiquitin proteasome system

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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