Hsp70 reduces α-synuclein aggregation and toxicity

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

Research output: Contribution to journalArticle

341 Citations (Scopus)

Abstract

Aggregation and cytotoxicity of misfolded α-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 α-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 α-synuclein in an α-synuclein transgenic mouse model and in an in vitro model of α-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding α-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble α-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble α-synuclein species and protected cells from α-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated α-synuclein species in vivo and in vitro and protect it from α-synuclein-dependent toxicity.

Original languageEnglish (US)
Pages (from-to)25497-25502
Number of pages6
JournalJournal of Biological Chemistry
Volume279
Issue number24
DOIs
StatePublished - Jun 11 2004
Externally publishedYes

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Synucleins
Toxicity
Agglomeration
Lewy Body Disease
Molecular Chaperones
Octoxynol
Detergents
Transgenic Mice
Molecular Weight
Molecular weight
Neocortex
Cytotoxicity
Electrophoresis
Neurodegenerative Diseases
Breeding
Parkinson Disease

ASJC Scopus subject areas

  • Biochemistry

Cite this

Hsp70 reduces α-synuclein aggregation and toxicity. / Klucken, Jochen; Shin, Youngah; Masliah, Eliezer; Hyman, Bradley T.; McLean, Pamela J.

In: Journal of Biological Chemistry, Vol. 279, No. 24, 11.06.2004, p. 25497-25502.

Research output: Contribution to journalArticle

Klucken, J, Shin, Y, Masliah, E, Hyman, BT & McLean, PJ 2004, 'Hsp70 reduces α-synuclein aggregation and toxicity', Journal of Biological Chemistry, vol. 279, no. 24, pp. 25497-25502. https://doi.org/10.1074/jbc.M400255200
Klucken, Jochen ; Shin, Youngah ; Masliah, Eliezer ; Hyman, Bradley T. ; McLean, Pamela J. / Hsp70 reduces α-synuclein aggregation and toxicity. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 24. pp. 25497-25502.
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