Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts From Patients With Huntington's Disease

Neurosci Bull. 2019 Dec;35(6):1024-1034. doi: 10.1007/s12264-019-00421-5. Epub 2019 Aug 20.


Huntington's disease (HD) is a deadly neurodegenerative disease with abnormal expansion of CAG repeats in the huntingtin gene. Mutant Huntingtin protein (mHTT) forms abnormal aggregates and intranuclear inclusions in specific neurons, resulting in cell death. Here, we tested the ability of a natural heat-shock protein 90 inhibitor, Gedunin, to degrade transfected mHTT in Neuro-2a cells and endogenous mHTT aggregates and intranuclear inclusions in both fibroblasts from HD patients and neurons derived from induced pluripotent stem cells from patients. Our data showed that Gedunin treatment degraded transfected mHTT in Neuro-2a cells, endogenous mHTT aggregates and intranuclear inclusions in fibroblasts from HD patients, and in neurons derived from induced pluripotent stem cells from patients in a dose- and time-dependent manner, and its activity depended on the proteasomal pathway rather than the autophagy route. These findings also showed that although Gedunin degraded abnormal mHTT aggregates and intranuclear inclusions in cells from HD patient, it did not affect normal cells, thus providing a new perspective for using Gedunin to treat HD.

Keywords: Degradation; Gedunin; Huntington’s disease; Mutant Huntingtin protein.

MeSH terms

  • Animals
  • Cell Culture Techniques
  • Fibroblasts / drug effects
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / metabolism
  • Humans
  • Huntingtin Protein / drug effects*
  • Huntingtin Protein / genetics
  • Huntington Disease / drug therapy*
  • Induced Pluripotent Stem Cells / drug effects
  • Intranuclear Inclusion Bodies / drug effects*
  • Leupeptins / pharmacology
  • Limonins / pharmacology*
  • Mice
  • Mutant Proteins / drug effects*
  • Mutation
  • Neurons / drug effects
  • Proteasome Endopeptidase Complex
  • Protein Aggregates / drug effects*
  • Transfection


  • Heat-Shock Proteins
  • Huntingtin Protein
  • Leupeptins
  • Limonins
  • Mutant Proteins
  • Protein Aggregates
  • gedunin
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde