Selective loss of nigral dopamine neurons induced by overexpression of truncated human α-synuclein in mice

2008 
Abstract Parkinson's disease is characterized by loss of nigral dopaminergic neurons and presence of Lewy bodies, whose major component is α-synuclein. In the present study, we generated transgenic mice termed Syn130m that express truncated human α-synuclein (amino acid residue number: 1–130) in dopaminergic neurons. Notably, dopaminergic neurons were selectively diminished in the substantia nigra pars compacta of Syn130m, while transgenic mice that expressed comparable amount of full-length human α-synuclein did not develop such pathology. Therefore, the truncation of human α-synuclein seems to be primarily responsible for the loss of nigral dopaminergic neurons. The nigral pathology resulted in impairment of axon terminals in the striatum and concomitant decrease in striatal dopamine content. Behaviorally, spontaneous locomotor activities of Syn130m were reduced, but the abnormality was ameliorated by treatment with L-DOPA. The loss of nigral dopaminergic neurons was not progressive and seemed to occur during embryogenesis along with the onset of expression of the transgene. Our results indicate that truncated human α-synuclein is deleterious to the development and/or survival of nigral dopaminergic neurons.
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