Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity

Karin M. Danzer, Wolfgang P. Ruf, Preeti Putcha, Daniel Joyner, Tadafumi Hashimoto, Charles Glabe, Bradley T. Hyman, Pamela J. McLean

Research output: Contribution to journalArticle

194 Scopus citations

Abstract

The paradoxical appearance of aggregated α-synuclein (αsyn) in naive transplanted embryonic stem cells in Parkinson's disease (PD) brains has recently been reported, highlighting the possibility of neuron to neuron transmission of αsyn in PD. Here, we demonstrate in a cellular model the presence of αsyn oligomers in the extracellular space, their uptake by neurons, retrograde axonal transport to cell soma, and detrimental effects on neighboring cells. Moreover, we demonstrate that Hsp70 chaperones αsyn in the extracellular space and reduces extracellular αsyn oligomer formation and related toxicity. These novel findings provide evidence that extracellular αsyn oligomers may represent a crucial player in the propagation of pathology in PD, with their modulation by Hsp70 representing a potential new target for therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)326-336
Number of pages11
JournalFASEB Journal
Volume25
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Aggregation
  • Microfluidic culture system
  • Parkinson's disease
  • Protein complementation

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Danzer, K. M., Ruf, W. P., Putcha, P., Joyner, D., Hashimoto, T., Glabe, C., Hyman, B. T., & McLean, P. J. (2011). Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity. FASEB Journal, 25(1), 326-336. https://doi.org/10.1096/fj.10-164624