The Lipase Activity of Phospholipase D2 is Responsible for Nigral Neurodegeneration in a Rat Model of Parkinson's Disease.
The Lipase Activity of Phospholipase D2 is Responsible for Nigral Neurodegeneration in a Rat Model of Parkinson's Disease.
复制标题
磷脂酶 D2 的脂肪酶活性导致帕金森病大鼠模型中的黑质神经变性。
DOI：
10.1016/j.neuroscience.2018.02.047
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发表时间：
2018
期刊：
影响因子：
3.3
通讯作者：
Muzyczka,Nicholas
中科院分区：
文献类型：
--
作者：
Mendez-Gomez,HectorR;Singh,Jasbir;Meyers,Craig;Chen,Weijun;Gorbatyuk,OlegS;Muzyczka,Nicholas
磷脂酶D2(PLD2)是一种参与囊泡运输和膜信号转导的酶，它与α-突触核蛋白相互作用，后者是一种已知在帕金森病(PD)发生发展中起作用的蛋白质。我们之前曾报道，PLD2在大鼠黑质致密部(SNc)过表达导致多巴胺神经元的快速神经变性，并且α-突触核蛋白抑制PLD2诱导的黑质变性(Gorbatyuk等人，2010年)。在此，我们报告PLD2的毒性是由于其脂肪酶活性所致。过表达PLD2的催化失活突变体(K758R)可以防止黑质中多巴胺能神经元的丢失，并且在过表达10 周后没有显示出毒性迹象。此外，突变体K758R不影响纹状体中的多巴胺水平。相反，阻止PLD2与动力蛋白或生长因子受体结合蛋白2(Grb2)相互作用但保留脂肪酶活性的突变体，继续表现出快速的神经退化。这些发现表明，PLD2与Dynamin的相互作用以及PLD2与Grb2的相互作用都不是神经变性的主要原因。Dynamin参与囊泡运输，而Grb2在细胞周期控制、趋化和激活酪氨酸激酶复合体方面具有多重作用。相反，磷脂酸(PLD2的产物)的合成似乎是PLD2诱导神经退化的关键，磷脂酸是多个细胞通路中的第二信使。α-突触核蛋白是PLD2活性的调节者，这一事实表明，PLD2活性的调节在PD的进展中可能是重要的。
Phospholipase D2 (PLD2), an enzyme involved in vesicle trafficking and membrane signaling, interacts with α-synuclein, a protein known to contribute in the development of Parkinson disease (PD). We previously reported that PLD2 overexpression in rat substantia nigra pars compacta (SNc) causes a rapid neurodegeneration of dopamine neurons, and that α-synuclein suppresses PLD2-induced nigral degeneration (Gorbatyuk et al., 2010). Here, we report that PLD2 toxicity is due to its lipase activity. Overexpression of a catalytically inactive mutant (K758R) of PLD2 prevents the loss of dopaminergic neurons in the SNc and does not show signs of toxicity after 10 weeks of overexpression. Further, mutant K758R does not affect dopamine levels in the striatum. In contrast, mutants that prevent PLD2 interaction with dynamin or growth factor receptor bound protein 2 (Grb2) but retained lipase activity, continued to show rapid neurodegeneration. These findings suggest that neither the interaction of PLD2 with dynamin, which has a role in vesicle trafficking, nor the PLD2 interaction with Grb2, which has multiple roles in cell cycle control, chemotaxis and activation of tyrosine kinase complexes, are the primary cause of neurodegeneration. Instead, the synthesis of phosphatidic acid (the product of PLD2), which is a second messenger in multiple cellular pathways, appears to be the key to PLD2 induced neurodegeneration. The fact that α-synuclein is a regulator of PLD2 activity suggests that regulation of PLD2 activity could be important in the progression of PD.