Geldanamycin induces heat shock protein 70 and protects against MPTP-induced dopaminergic neurotoxicity in mice.
As key molecular chaperone proteins, heat shock proteins (HSPs) represent an important cellular protective mechanism against neuronal cell death in various models of neurological disorders. In this study, we investigated the effect as well as the molecular mechanism of geldanamycin (GA), an inhibitor of Hsp90, on 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a mouse model of Parkinson disease. Neurochemical analysis showed that pretreatment with GA (via intracerebral ventricular injection 24 h prior to MPTP treatment) increased residual dopamine content and tyrosine hydroxylase immunoreactivity in the striatum 24 h after MPTP treatment. To dissect out the molecular mechanism underlying this neuroprotection, we showed that the GA-mediated protection against MPTP was associated with a reduction of cytosolic Hsp90 and an increase in Hsp70, with no significant changes in Hsp40 and Hsp25 levels. Furthermore, in parallel with the induction of Hsp70, striatal nuclear HSF1 levels and HSF1 binding to heat shock element sites in the Hsp70 promoter were significantly enhanced by the GA pretreatment. Together these results suggested that the molecular cascade leading to the induction of Hsp70 is critical to the neuroprotection afforded by GA against MPTP-induced neurotoxicity in the brain and that pharmacological inhibition of Hsp90 may represent a potential therapeutic strategy for Parkinson disease.
Shen
Hai-Ying
HY
Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
He
Jin-Cai
JC
Wang
Yumei
Y
Huang
Qing-Yuan
QY
Chen
Jiang-Fan
JF
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000737:chemistry*; D000818:Animals; D016227:Benzoquinones; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D016923:Cell Death; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000737:chemistry*; D015259:Dopamine Agents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D047029:Lactams, Macrocyclic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry; D009363:Neoplasm Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009498:Neurotoxins / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology; D011809:Quinones / Q000494:pharmacology*; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000737:chemistry; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C490017:Hsf1 protein, mouse; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D009498:Neurotoxins; D011809:Quinones; D014157:Transcription Factors; D014443:Tyrosine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; C001277:geldanamycin