Dopaminergic Loss and Inclusion Body Formation in α-Synuclein Mice: Implications for Neurodegenerative Disorders

To elucidate the role of the synaptic protein α-synuclein in neurodegenerative disorders, transgenic mice expressing wild-type human α-synuclein were generated. Neuronal expression of human α-synuclein resulted in progressive accumulation of α-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 α-synuclein may play a causal role in Parkinson's disease and related conditions.