Transgenic Mice Overexpressing Tyrosine-to-Cysteine Mutant Human α-Synuclein A PROGRESSIVE NEURODEGENERATIVE MODEL OF DIFFUSE LEWY BODY DISEASE

Abstract Abnormal aggregation of human α-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 α-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 α-synuclein fibril formation and neurotoxicity. In the current study, we have generated transgenic mice expressing the Y39C mutant human α-synuclein gene controlled by the mouse Thy1 promoter. Mutant human α-synuclein was widely expressed in transgenic mouse brain, resulting in 150% overexpression relative to endogenous mouse α-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 α-synuclein oligomers, associated with worse motor function and cognitive impairment in the Morris water maze. By age 21–24 months, α-synuclein aggregates were further increased, accompanied by severe behavioral deficits. At this age, transgenic mice developed neuropathology, such as Lewy body-like α-synuclein and ubiquitin-positive inclusions, phosphorylation at Ser129 of human α-synuclein, and increased apoptotic cell death. In summary, Y39C human α-synuclein transgenic mice show age-dependent, progressive neuronal degeneration with motor and cognitive deficits similar to diffuse Lewy body disease. The time course of α-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.