Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease.
Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease.
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DOI：
10.1007/s13238-015-0230-9
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发表时间：
2016-02
期刊：
影响因子：
21.1
通讯作者：
Chen Q
中科院分区：
文献类型：
--
作者：
Song P;Li S;Wu H;Gao R;Rao G;Wang D;Chen Z;Ma B;Wang H;Sui N;Deng H;Zhang Z;Tang T;Tan Z;Han Z;Lu T;Zhu Y;Chen Q
Parkin是一种E3泛素连接酶，其突变或失活分别与家族性或散发性帕金森病（PD）相关，表现为黑质（SN）和纹状体（STR）区域神经元细胞的选择性脆弱性。然而，潜在的分子机制与帕金森病的病因帕金仍然难以捉摸。在这里，我们报告，p62，蛋白质质量控制，包涵体形成，选择性自噬和多种信号通路的关键调节器，是帕金蛋白的一种新底物。在parkin基因敲除小鼠中，SN和STR区域的P62水平增加，但在其他脑区没有增加。帕金直接与p62相互作用并在K13处泛素化p62，以促进p62的蛋白酶体降解，即使在不存在ATG 5的情况下也是如此。致病性突变、parkin的敲低或p62在K13处的突变阻止了p62的降解。我们进一步表明，帕金缺乏症小鼠有明显的损失酪氨酸羟化酶阳性神经元，并有更差的表现，在运动测试时，与6-羟基多巴胺盐酸盐在老年小鼠。这些结果表明，除了在调节自噬中的关键作用，p62受到parkin介导的蛋白酶体降解，并暗示parkin/p62轴的失调可能涉及在PD发病过程中神经细胞的选择性脆弱性。本文的在线版本（doi：10.1007/s13238-015-0230-9）包含补充材料，可供授权用户使用。
Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson’s disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis. The online version of this article (doi:10.1007/s13238-015-0230-9) contains supplementary material, which is available to authorized users.