Protective role of heat shock and heat shock protein 70 in lactacystin-induced cell death both in the rat substantia nigra and PC12 cells.
Proteasomal dysfunction plays an important role in the pathogenesis of Parkinson disease (PD). Although clinical and experimental evidence continues to accumulate indicating heat shock protein 70 (HSP70) is significant in the pathogenesis of PD, few studies have been made to investigate the role of HSP70 under the condition of proteasome dysfunction. In in vivo study, we infused lactacystin into the unilateral substantia nigra (SN) of Sprague-Dawley rats with or without preceding whole body hyperthermia (WBH). Immunohistochemical studies showed the death of dopaminergic neurons and activated microglia in the SN. Lactacystin with prior WBH increased the expression of HSP70 more than did lactacystin alone and decreased lactacystin-induced dopaminergic neuronal death in the SN. In PC12 cells, heat shock pretreatment decreased lactacystin-induced cell death. Although additional treatment of nocodazole, ammonium chloride, and 3-methyladenine augmented cell death by lactacystin, heat shock pretreated to these drugs offsets their additional toxicity. These results indicate that heat shock proteins, especially HSP70, could play an important role under the condition of proteasome dysfunction in part by fostering aggresome formation and lysosome-mediated autophagy.
Ahn
Tae-Beom
TB
Department of Neurology, Kyung Hee University College of Medicine, South Korea.
Jeon
Beom S
BS
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D050884:HSP72 Heat-Shock Proteins / Q000502:physiology*; D018869:Heat-Shock Response / Q000502:physiology*; D006979:Hyperthermia, Induced / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009474:Neurons / Q000187:drug effects*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D050884:HSP72 Heat-Shock Proteins; C067713:lactacystin; D014446:Tyrosine 3-Monooxygenase; D000111:Acetylcysteine