Substrate-mediated enhancement of phosphorylated tyrosine hydroxylase in nigrostriatal dopamine neurons:: evidence for a role of α-synuclein
Substrate-mediated enhancement of phosphorylated tyrosine hydroxylase in nigrostriatal dopamine neurons:: evidence for a role of α-synuclein
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DOI：
10.1111/j.1471-4159.2005.03606.x
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Goudreau, JL
中科院分区：
文献类型：
--
作者：
Drolet, RE;Behrouz, B;Goudreau, JL
比较了丝氨酸-40、丝氨酸-31和丝氨酸-19磷酸化的酪氨酸羟化酶(TH)蛋白在基础条件下以及野生型和纯合型α-突触核蛋白敲除小鼠激活的黑质纹状体多巴胺(NSDA)神经元中的酶催化活性。在存在或不存在补充L酪氨酸的情况下，小鼠被注射D2拮抗剂雷氯必利来刺激NSDA神经元的活动。在基础条件下或在拉氯普利诱导的NSDA活性加速后，野生型和α-突触核蛋白基因敲除小鼠之间的磷酸化TH水平或TH催化活性没有差异。在野生型动物中，给予酪氨酸增强了雷氯普利诱导的磷酸化TH和酶活性的增加。然而，在α-突触核蛋白基因敲除小鼠中，酪氨酸注射并没有增加雷氯普利刺激的NSDA神经元中磷酸化TH水平或酶催化活性。这些发现表明，α-突触核蛋白在酪氨酸在加速神经元活动过程中增强TH磷酸化或抑制TH失活的能力中发挥作用。本研究支持α-突触核蛋白作为分子伴侣蛋白的假设，以底物和活性依赖的方式调节TH的磷酸化状态。
Tyrosine hydroxylase (TH) protein, phosphorylated at serine-40, serine-31 and serine-19, and enzyme catalytic activity were compared under basal conditions and in activated nigrostriatal dopamine (NSDA) neurons of wild-type and homozygous alpha-synuclein knockout mice. Mice were injected with the D2 antagonist raclopride to stimulate NSDA neuronal activity in the presence or absence of supplemental L-tyrosine. There was no difference in phosphorylated TH levels or TH catalytic activity between wild-type and alpha-synuclein knockout mice under basal conditions or following raclopride-induced acceleration of NSDA activity. In wild-type animals, tyrosine administration potentiated the raclopride-induced increase in phosphorylated TH and enzyme activity. However, tyrosine administration did not enhance phosphorylated TH levels or enzyme catalytic activity in raclopride-stimulated NSDA neurons in alpha-synuclein knockout mice. These findings suggest that alpha-synuclein plays a role in the ability of tyrosine to either enhance TH phosphorylation or hinder TH inactivation during accelerated neuronal activity. The present study supports the hypothesis that alpha-synuclein functions as a molecular chaperone protein that regulates the phosphorylation state of TH in a substrate and activity-dependent manner.