Intracellular degradation of misfolded tau protein induced by geldanamycin is associated with activation of proteasome

J Alzheimers Dis. 2013;33(2):339-48. doi: 10.3233/JAD-2012-121072.


Misfolded, N- and C-terminally truncated tau protein is the primary constituent of neurofibrillary tangles in brains of patients afflicted with Alzheimer's disease (AD). Intracellular accumulation of misfolded and truncated tau leads to generation of cytotoxic intermediates; transgenic expression of truncated tau leads to neurological deficits, neurofibrillary degeneration, and premature death of animals. Since no cure for AD or other tauopathies is available yet, we tested the possibility for prevention of pathogenic events elicited by tau, via inhibition of its intracellular accumulation. Using a cell model conditionally expressing truncated and misfolding-prone tau protein, we showed that pathogenic forms of tau are degraded via the proteasome. We have also observed that chymotrypsin-like activity of the proteasome was significantly suppressed (a decrease of ∼29.12% in comparison to control cells; p < 0.001) as a consequence of truncated tau expression. Interestingly, the activity of the proteasome was enhanced by geldanamycin, a natural inhibitor of Hsp90. This activation resulted in accelerated degradation of misfolded tau. We suggest that non-toxic inhibitors of Hsp90, especially those which can activate the proteasome, are good candidates for the development of molecules that efficiently counteract the damaging effects of pathologically misfolded proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoquinones / toxicity*
  • COS Cells
  • Cell Line, Tumor
  • Chlorocebus aethiops
  • Chymotrypsin / metabolism
  • Cysteine Proteinase Inhibitors / toxicity
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Lactams, Macrocyclic / toxicity*
  • Neuroblastoma
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology*
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Folding
  • Proteostasis Deficiencies / chemically induced
  • Proteostasis Deficiencies / metabolism*
  • Proteostasis Deficiencies / pathology
  • Tauopathies / chemically induced
  • Tauopathies / metabolism*
  • Tauopathies / pathology
  • Transgenes / genetics
  • tau Proteins / chemistry
  • tau Proteins / genetics
  • tau Proteins / metabolism*


  • Benzoquinones
  • Cysteine Proteinase Inhibitors
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • tau Proteins
  • Chymotrypsin
  • Proteasome Endopeptidase Complex
  • geldanamycin