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Science 2000 Feb 18;287(5456):1265-1269 Dopaminergic Loss and Inclusion Body Formation in alpha-Synuclein Mice: Implications for Neurodegenerative Disorders. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L Department of Neurosciences, Department of Pathology, University of California San Diego, La Jolla, CA 92093-0624, USA. Department of Psychiatry, Yokohama City University, School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236, Japan. Gladstone Institute of Neurological Disease and Department of Neurology, University of California San Francisco, Post Office Box 419100, San Francisco, CA 94141-9100, USA. To elucidate the role of the synaptic protein alpha-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human alpha-synuclein were generated. Neuronal expression of human alpha-synuclein resulted in progressive accumulation of alpha-synuclein-and ubiquitin-immunoreactive inclusions in neurons in the neocortex, hippocampus, and substantia nigra. Ultrastructural analysis revealed both electron-dense intranuclear deposits and cytoplasmic inclusions. These alterations were associated with loss of dopaminergic terminals in the basal ganglia and with motor impairments. These results suggest that accumulation of wild-type alpha-synuclein may play a causal role in Parkinson's disease and related conditions.