Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders
Eliezer Masliah(University of California San Diego), Edward Rockenstein, Isaac Veinbergs(University of California San Diego), Margaret Mallory, Makoto Hashimoto, Ayako Takeda(Yokohama City University), Yutaka Sagara(University of California San Diego), Abbyann Sisk(University of California San Diego), Lennart Mucke(Gladstone Institutes)
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Abstract
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.
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