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J. Biol. Chem., Vol. 280, Issue 48, 39962-39969, December 2, 2005

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Geldanamycin Induces Heat Shock Protein 70 and Protects against MPTP-induced Dopaminergic Neurotoxicity in Mice^*

Hai-Ying Shen1, Jin-Cai He12, Yumei Wang, Qing-Yuan Huang, and Jiang-Fan Chen3

From the Molecular Neuropharmacology Laboratory, Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118 and the Department of Neurology, the Affiliated First Teaching Hospital, and Experimental Neurobiology Research Institute, Wenzhou Medical College, Wenzhou 325000, China

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.

Received for publication, May 20, 2005 , and in revised form, September 13, 2005.

^* This work was supported by the National Institutes of Health grants (NS37403 and NS41083) and the Bumpus Foundation (JFC). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Supported in part by a special funding from the Wenzhou Medical College.

³ To whom correspondence should be addressed: Dept. of Neurology, Boston University School of Medicine, 715 Albany St., E301, Boston, MA 02118. Tel.: 617-414-1249; Fax: 617-638-5354; E-mail: chenjf{at}bu.edu.

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