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

The paradoxical appearance of aggregated alpha-synuclein (alpha syn) 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 alpha syn in PD. Here, we demonstrate in a cellular model the presence of alpha syn 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 alpha syn in the extracellular space and reduces extracellular alpha syn oligomer formation and related toxicity. These novel findings provide evidence that extracellular alpha syn 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.-Danzer, K. M., Ruf, W. P., Putcha, P., Joyner, D., Hashimoto, T., Glabe, C., Hyman, B. T., McLean, P. J. Heat-shock protein 70 modulates toxic extracellular alpha-synuclein oligomers and rescues trans-synaptic toxicity. FASEB J. 25, 326-336 (2011). www.fasebj.org