Nitrated alpha-synuclein induces the loss of dopaminergic neurons in the substantia nigra of rats

• Published in: PloS one 2010-04, Vol.5 (4), p.e9956
• Main Authors: Yu, Zhongwang, Xu, Xiaohui, Xiang, Zhenghua, Zhou, Jianfeng, Zhang, Zhaohuan, Hu, Chun, He, Cheng
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - pharmacology; alpha-Synuclein - toxicity; Animals; Apoptosis; Axons; Biochemistry/Chemical Biology of the Cell; Biochemistry/Macromolecular Chemistry; Biocompatibility; Cell Biology/Cellular Death and Stress Responses; Cell death; Cell Death - drug effects; Cells, Cultured; Degeneration; Dopamine; Dopamine D2 receptors; Down-Regulation - genetics; Etiology; Gait Disorders, Neurologic - chemically induced; Inclusions; Kinases; Lewy bodies; Locomotion; Movement disorders; Neostriatum; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - pathology; Neuroscience/Neurobiology of Disease and Regeneration; Neurosciences; Nitrates - pharmacology; Nitrates - toxicity; Nitration; Parkinson Disease - etiology; Parkinson's disease; Pathogenesis; Rats; Receptors, Dopamine D2 - genetics; Rodents; Substantia nigra; Substantia Nigra - pathology; Synuclein
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0009956

The pathology of Parkinson's disease (PD) is characterized by the degeneration of the nigrostriatal dopaminergic pathway, as well as the formation of intraneuronal inclusions known as Lewy bodies and Lewy neurites in the substantia nigra. Accumulations of nitrated alpha-synuclein are demonstrated in the signature inclusions of Parkinson's disease. However, whether the nitration of alpha-synuclein is relevant to the pathogenesis of PD is unknown. In this study, effect of nitrated alpha-synuclein to dopaminergic (DA) neurons was determined by delivering nitrated recombinant TAT-alpha-synuclein intracellular. We provide evidence to show that the nitrated alpha-synuclein was toxic to cultured dopaminergic SHSY-5Y neurons and primary mesencephalic DA neurons to a much greater degree than unnitrated alpha-synuclein. Moreover, we show that administration of nitrated alpha-synuclein to the substantia nigra pars compacta of rats caused severe reductions in the number of DA neurons therein, and led to the down-regulation of D(2)R in the striatum in vivo. Furthermore, when administered to the substantia nigra of rats, nitrated alpha-synuclein caused PD-like motor dysfunctions, such as reduced locomotion and motor asymmetry, however unmodified alpha-synuclein had significantly less severe behavioral effects. Our results provide evidence that alpha-synuclein, principally in its nitrated form, induce DA neuron death and may be a major factor in the etiology of PD.