Initiation and synergistic fibrillization of tau and alpha-synuclein.
Alpha-synuclein (alpha-syn) and tau polymerize into amyloid fibrils and form intraneuronal filamentous inclusions characteristic of neurodegenerative diseases. We demonstrate that alpha-syn induces fibrillization of tau and that coincubation of tau and alpha-syn synergistically promotes fibrillization of both proteins. The in vivo relevance of these findings is grounded in the co-occurrence of alpha-syn and tau filamentous amyloid inclusions in humans, in single transgenic mice that express A53T human alpha-syn in neurons, and in oligodendrocytes of bigenic mice that express wild-type human alpha-syn plus P301L mutant tau. This suggests that interactions between alpha-syn and tau can promote their fibrillization and drive the formation of pathological inclusions in human neurodegenerative diseases.
Giasson
Benoit I
BI
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine.
Forman
Mark S
MS
Higuchi
Makoto
M
Golbe
Lawrence I
LI
Graves
Charles L
CL
Kotzbauer
Paul T
PT
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001704:Biopolymers; D001923:Brain Chemistry; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D009474:Neurons / Q000737:chemistry; D009836:Oligodendroglia / Q000737:chemistry; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D051843:Synucleins; D024801:Tauopathies / Q000378:metabolism; D051844:alpha-Synuclein; D016875:tau Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism
D000682:Amyloid; D001704:Biopolymers; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein; D016875:tau Proteins