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J. Biol. Chem., Vol. 279, Issue 24, 25497-25502, June 11, 2004

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Hsp70 Reduces -Synuclein Aggregation and Toxicity^*

Jochen Klucken, Youngah Shin, Eliezer Masliah, Bradley T. Hyman, and Pamela J. McLean¶

From the Alzheimer's Disease Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129 and the Department of Neurosciences, University of California San Diego, School of Medicine, La Jolla, California 92093

Aggregation and cytotoxicity of misfolded -synuclein is postulated to be crucial in the disease process of neurodegenerative disorders such as Parkinson's disease and DLB (dementia with Lewy bodies). In this study, we detected misfolded and aggregated -synuclein in a Triton X-100 insoluble fraction as well as a high molecular weight product by gel electrophoresis of temporal neocortex from DLB patients but not from controls. We also found similar Triton X-100 insoluble forms of -synuclein in an -synuclein transgenic mouse model and in an in vitro model of -synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding -synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble -synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble -synuclein species and protected cells from -synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated -synuclein species in vivo and in vitro and protect it from -synuclein-dependent toxicity.

Received for publication, January 9, 2004 , and in revised form, March 24, 2004.

^* This work was supported by the National Institutes of Health Grants NS38372 and AG18440, Deutsche Forschungsgemeinschaft KL 1395/2-1, the Harvard Brain Tissue Resource Center Grant 1R24MH68855, the National Institutes of Health Grant AG05134-20 (to the Massachusetts Alzheimer's Disease Research Center), and National Institutes of Health Grant NS38372A-06 (to the Massachusetts General Hospital-Massachusetts Institutes of Technology Udall Center Brain Bank). 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.

^¶ To whom correspondence should be addressed. Tel.: 617-726-1263; Fax: 617-724-1480; E-mail: pmclean{at}partners.org.

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