LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration.
LK6/Mnk2a is a new kinase of alpha synuclein phosphorylation mediating neurodegeneration.
复制标题
LK6/Mnk2a 是介导神经退行性变的 α 突触核蛋白磷酸化的新激酶。
DOI：
10.1038/srep12564
复制
发表时间：
2015-07-29
影响因子：
4.6
通讯作者：
Wen T
中科院分区：
文献类型：
--
作者：
Zhang S;Xie J;Xia Y;Yu S;Gu Z;Feng R;Luo G;Wang D;Wang K;Jiang M;Cheng X;Huang H;Zhang W;Wen T
帕金森病（Parkinson's disease，PD）是一种由于黑质多巴胺能（dopaminergic，DA）神经元丢失而引起的运动障碍。α-突触核蛋白磷酸化和α-突触核蛋白包涵体（Lewy小体）成为主要的贡献者，但对其形成机制知之甚少。在这里，我们使用蛋白质表达谱的PD构建一个模型，他们的信号网络从果蝇到人类和提名的主要节点，调节PD的发展。我们在这个网络中发现，LK 6，一个丝氨酸/苏氨酸蛋白激酶，通过鉴定LK 6敲除和过表达，在促进α-突触核蛋白Ser 129磷酸化中起关键作用。体内实验进一步证实，LK 6确实能增强α-synuclein的磷酸化，加速多巴胺能神经元的死亡，降低果蝇的攀爬能力，缩短果蝇的寿命。此外，MAP激酶相互作用激酶2a（Mnk 2a）（LK 6的人类同源物）也显示出使α-突触核蛋白磷酸化并导致α-突触核蛋白包涵体形成。在其作用机制上，PMA的激活和PD 98059的抑制是通过ERK信号通路调控LK 6和Mnk 2a介导的磷酸化。我们的发现确立了Lk 6和Mnk 2a在前所未有的信号网络中的关键作用，可能导致预防α-突触核蛋白包涵体形成和神经退行性变的新疗法。
Parkinson’s disease (PD) is a movement disorder due to the loss of dopaminergic (DA) neurons in the substantia nigra. Alpha-synuclein phosphorylation and α-synuclein inclusion (Lewy body) become a main contributor, but little is known about their formation mechanism. Here we used protein expression profiling of PD to construct a model of their signalling network from drsophila to human and nominate major nodes that regulate PD development. We found in this network that LK6, a serine/threonine protein kinase, plays a key role in promoting α-synuclein Ser129 phosphorylation by identification of LK6 knockout and overexpression. In vivo test was further confirmed that LK6 indeed enhances α-synuclein phosphorylation, accelerates the death of dopaminergic neurons, reduces the climbing ability and shortens the the life span of drosophila. Further, MAP kinase-interacting kinase 2a (Mnk2a), a human homolog of LK6, also been shown to make α-synuclein phosphorylation and leads to α-synuclein inclusion formation. On the mechanism, the phosphorylation mediated by LK6 and Mnk2a is controlled through ERK signal pathway by phorbolmyristate acetate (PMA) avtivation and PD98059 inhibition. Our findings establish pivotal role of Lk6 and Mnk2a in unprecedented signalling networks, may lead to new therapies preventing α-synuclein inclusion formation and neurodegeneration.