Heat-shock protein 70 modulates toxic extracellular α-synuclein oligomers and rescues trans-synaptic toxicity.
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.
Danzer
Karin M
KM
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, 114 16th St., Charlestown, MA 02129, USA.
Ruf
Wolfgang P
WP
Putcha
Preeti
P
Joyner
Daniel
D
Hashimoto
Tadafumi
T
Glabe
Charles
C
Hyman
Bradley T
BT
McLean
Pamela J
PJ
D000818:Animals; D001369:Axons / Q000378:metabolism; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000229:Dependovirus / Q000235:genetics; D005110:Extracellular Space / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D055503:Protein Multimerization; D009435:Synaptic Transmission / Q000502:physiology*; D014162:Transfection; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D016227:Benzoquinones; D017077:Culture Media, Conditioned; D018840:HSP70 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D051844:alpha-Synuclein; D049452:Green Fluorescent Proteins; C112765:tanespimycin; D008156:Luciferases