Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein.
alpha-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that alpha-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human alpha-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, alpha-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal alpha-synuclein inclusions paralleling disease onset, and the alpha-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the alpha-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T alpha-synuclein leads to the formation of toxic filamentous alpha-synuclein neuronal inclusions that cause neurodegeneration.
Giasson
Benoit I
BI
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, 3600 Spruce Street, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Duda
John E
JE
Quinn
Shawn M
SM
Zhang
Bin
B
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009069:Movement Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D012995:Solubility; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051843:Synucleins; D014855:Wallerian Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051844:alpha-Synuclein
D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C497604:SNCA protein, human; C497605:Snca protein, mouse; D051843:Synucleins; D051844:alpha-Synuclein