Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons.
Parkinson Sac Domain Mutation in Synaptojanin 1 Impairs Clathrin Uncoating at Synapses and Triggers Dystrophic Changes in Dopaminergic Axons.
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DOI：
10.1016/j.neuron.2017.01.019
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发表时间：
2017-02-22
期刊：
影响因子：
16.2
通讯作者：
De Camilli P
中科院分区：
文献类型：
--
作者：
Cao M;Wu Y;Ashrafi G;McCartney AJ;Wheeler H;Bushong EA;Boassa D;Ellisman MH;Ryan TA;De Camilli P
突触素1(Synaptojanin 1，SJ1)是一种主要的突触前磷酸酶，它将突触小泡的内吞作用与PI(4，5)P2的去磷酸化结合在一起，这一反应是内吞因子从细胞膜上脱落所必需的。虽然SJ1的S 5-磷酸酶模块在这一过程中的作用已被证实，但其SAC磷酸酶结构域的作用仍不清楚，其首选底物为PI4P。最近，在早发性帕金森病患者中发现了其SAC区域的纯合子突变。我们发现，携带这种突变的小鼠出现了与人类患者相似的神经学表现。这些小鼠的突触表现出内吞缺陷和显着的网状蛋白包裹的中间产物的积累，强烈暗示SAC结构域在内吞蛋白动力学中的活性。突变的大脑中生长素(PARK19)和帕金素(PARK2)水平升高。此外，在背侧纹状体的多巴胺能轴突中选择性地观察到营养不良的轴突终末改变。这些结果加强了突触内皮细胞功能障碍与帕金森氏症之间联系的证据。
Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1’s 5-phosphatase module in this process is well established, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset Parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients. Synapses of these mice displayed endocytic defects and a striking accumulation of clathrin coated intermediates strongly implicating Sac domain’s activity in endocytic protein dynamics. Mutant brains had elevated auxilin (PARK19) and parkin (PARK2) levels. Moreover, dystrophic axonal terminal changes were selectively observed in dopaminergic axons in the dorsal striatum. These results strengthen evidence for a link between synaptic endocytic dysfunction and Parkinson’s disease.