Common anti-apoptotic roles of parkin and alpha-synuclein in human dopaminergic cells.
Common anti-apoptotic roles of parkin and alpha-synuclein in human dopaminergic cells.
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发表时间：
2005
影响因子：
3.1
通讯作者：
Y. Machida;T. Chiba;A. Takayanagi;Yoshikazu Tanaka;M. Asanuma;N. Ogawa;A. Koyama;T. Iwatsubo;S. Ito;Poul Hening Jansen;N. Shimizu;Keiji Tanaka;Y. Mizuno;N. Hattori
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文献类型：
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作者：
Y. Machida;T. Chiba;A. Takayanagi;Yoshikazu Tanaka;M. Asanuma;N. Ogawa;A. Koyama;T. Iwatsubo;S. Ito;Poul Hening Jansen;N. Shimizu;Keiji Tanaka;Y. Mizuno;N. Hattori
Parkin基因是常染色体隐性遗传性幼年型帕金森综合征（AR-JP）基因的产物，在帕金森病（PD）的发病过程中起重要作用。尽管许多研究，包括寻找帕金作为E3泛素蛋白连接酶的底物，但帕金功能丧失诱导选择性多巴胺能神经元死亡的机制仍不清楚。与这个问题相关，在这里，我们表明parkin的反义敲低导致与半胱天冬酶激活相关的人多巴胺能SH-SY 5 Y细胞的凋亡性细胞死亡，并伴随着由于DOPA和DA的自氧化引起的氧化性多巴胺（DA）代谢物的积累。（α-SN），另一种家族性PD基因产物，防止氧化性DOPA/DA代谢物的积累和由parkin损失引起的细胞死亡。我们的研究结果表明，parkin和α-SN在DA代谢中有一个共同的途径，其异常导致氧化DA代谢产物的积累和随后的细胞死亡。
Parkin, a product of the gene responsible for autosomal recessive juvenile parkinsonism (AR-JP), is an important player in the pathogenic process of Parkinson's disease (PD). Despite numerous studies including search for the substrate of parkin as an E3 ubiquitin-protein ligase, the mechanism by which loss-of-function of parkin induces selective dopaminergic neuronal death remains unclear. Related to this issue, here we show that antisense knockdown of parkin causes apoptotic cell death of human dopaminergic SH-SY5Y cells associated with caspase activation and accompanied by accumulation of oxidative dopamine (DA) metabolites due to auto-oxidation of DOPA and DA. Forced expression of alpha-synuclein (alpha-SN), another familial PD gene product, prevented accumulation of oxidative DOPA/DA metabolites and cell death caused by parkin loss. Our findings indicate that both parkin and alpha-SN share a common pathway in DA metabolism whose abnormality leads to accumulation of oxidative DA metabolites and subsequent cell death.