title: Transgenic mice overexpressing tyrosine-to-cysteine mutant human alpha-synuclein: a progressive neurodegenerative model of diffuse Lewy body disease.
abstract: Abnormal aggregation of human alpha-synuclein in Lewy bodies and Lewy neurites is a pathological hallmark of Parkinson disease and dementia with Lewy bodies. Studies have shown that oxidation and nitration of alpha-synuclein lead to the formation of stable dimers and oligomers through dityrosine cross-linking. Previously we have reported that tyrosine-to-cysteine mutations, particularly at the tyrosine 39 residue (Y39C), significantly enhanced alpha-synuclein fibril formation and neurotoxicity. In the current study, we have generated transgenic mice expressing the Y39C mutant human alpha-synuclein gene controlled by the mouse Thy1 promoter. Mutant human alpha-synuclein was widely expressed in transgenic mouse brain, resulting in 150% overexpression relative to endogenous mouse alpha-synuclein. At age 9-12 months, transgenic mice began to display motor dysfunction in rotarod testing. Older animals aged 15-18 months showed progressive accumulation of human alpha-synuclein oligomers, associated with worse motor function and cognitive impairment in the Morris water maze. By age 21-24 months, alpha-synuclein aggregates were further increased, accompanied by severe behavioral deficits. At this age, transgenic mice developed neuropathology, such as Lewy body-like alpha-synuclein and ubiquitin-positive inclusions, phosphorylation at Ser(129) of human alpha-synuclein, and increased apoptotic cell death. In summary, Y39C human alpha-synuclein transgenic mice show age-dependent, progressive neuronal degeneration with motor and cognitive deficits similar to diffuse Lewy body disease. The time course of alpha-synuclein oligomer accumulation coincided with behavioral and pathological changes, indicating that these oligomers may initiate protein aggregation, disrupt cellular function, and eventually lead to neuronal death.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Medicine, School of Medicine, University of Colorado-Denver, 4200 E. 9th Avenue, Denver, CO 80262, USA. wenbo.zhou@uchsc.edu
authors.forename: Wenbo
authors.initials: W
authors.lastname: Zhou
authors.forename: Julie B
authors.initials: JB
authors.lastname: Milder
authors.forename: Curt R
authors.initials: CR
authors.lastname: Freed
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019281:Dimerization; D004195:Disease Models, Animal; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism* / Q000473:pathology; D020961:Lewy Body Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D018800:Thy-1 Antigens / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018800:Thy-1 Antigens; D051844:alpha-Synuclein