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


RESULTS
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.


CONCLUSIONS
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.
Yu
Zhongwang
Z
Institute of Neuroscience and Key Laboratory of Molecular Neurobiology of Minister of Education, Neuroscience Research Center of Changzheng Hospital, Second Military Medical University, Shanghai, China.
Xu
Xiaohui
X
Xiang
Zhenghua
Z
Zhou
Jianfeng
J
Zhang
Zhaohuan
Z
Hu
Chun
C
He
Cheng
C
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004298:Dopamine; D015536:Down-Regulation / Q000235:genetics; D020233:Gait Disorders, Neurologic / Q000139:chemically induced; D009474:Neurons / Q000473:pathology*; D009566:Nitrates / Q000494:pharmacology* / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000235:genetics; D013378:Substantia Nigra / Q000473:pathology*; D051844:alpha-Synuclein / Q000494:pharmacology* / Q000633:toxicity
D009566:Nitrates; D017448:Receptors, Dopamine D2; D051844:alpha-Synuclein; D004298:Dopamine
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