Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity.
Aggregation and cytotoxicity of misfolded alpha-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 alpha-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 alpha-synuclein in an alpha-synuclein transgenic mouse model and in an in vitro model of alpha-synuclein aggregation. Introducing the molecular chaperone Hsp70 into the in vivo model by breeding alpha-synuclein transgenic mice with Hsp70-overexpressing mice led to a significant reduction in both the high molecular weight and detergent-insoluble alpha-synuclein species. Concomitantly, we found that Hsp70 overexpression in vitro similarly reduced detergent-insoluble alpha-synuclein species and protected cells from alpha-synuclein-induced cellular toxicity. Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated alpha-synuclein species in vivo and in vitro and protect it from alpha-synuclein-dependent toxicity.
Klucken
Jochen
J
Alzheimer's Disease Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Shin
Youngah
Y
Masliah
Eliezer
E
Hyman
Bradley T
BT
McLean
Pamela J
PJ
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology*; D006801:Humans; D020961:Lewy Body Disease / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000633:toxicity; D017830:Octoxynol / Q000494:pharmacology; D017510:Protein Folding; D051843:Synucleins; D051844:alpha-Synuclein
D018840:HSP70 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D017830:Octoxynol