The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway.
The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway.
复制标题
DOI：
10.1038/ncomms11803
复制
发表时间：
2016-06-09
影响因子：
16.6
通讯作者：
Rubinsztein DC
中科院分区：
文献类型：
--
作者：
Bento CF;Ashkenazi A;Jimenez-Sanchez M;Rubinsztein DC
帕金森病（PD）的形式与溶酶体和自噬功能障碍有关。在某些类型的早发性帕金森综合征中突变的ATP 13 A2已被认为是自噬-溶酶体途径的调节剂。然而，关于ATP 13 A2效应器以及它们如何调节这一通路的知之甚少。在这里，我们表明，ATP 13 A2消耗负调控另一个PD相关基因（SYT 11）在转录和翻译后水平。SYT 11转录的降低是由一种依赖于MYCBP 2诱导的TSC 2泛素化的机制控制的，这导致mTORC 1活化和TFEB介导的SYT 11转录的降低，而蛋白质周转的增加是由SYT 11泛素化和降解调节的。这两种机制都导致SYT 11水平降低，进而诱导溶酶体功能障碍和自噬体降解受损。因此，我们认为ATP 13 A2和SYT 11在自噬-溶酶体通路的调节中形成了一个新的功能网络，这可能有助于PD相关神经变性的形成。 ATP 13 A2突变与溶酶体功能障碍和早发性帕金森病相关。Bento等人在本文中表明，ATP 13 A2消耗在转录和翻译后水平上负调控SYT 11，这反过来又损害了自噬-溶酶体途径的功能。
Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy–lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation. Both mechanisms account for a decrease in the levels of SYT11, which, in turn, induces lysosomal dysfunction and impaired degradation of autophagosomes. Thus, we propose that ATP13A2 and SYT11 form a new functional network in the regulation of the autophagy–lysosome pathway, which is likely to contribute to forms of PD-associated neurodegeneration. Mutations in ATP13A2 are associated with lysosomal dysfunction and early onset Parkinson's disease. Here Bento et al. show that ATP13A2 depletion negatively regulates SYT11, at both transcriptional and post-translational levels, which in turn impairs function of the autophagy-lysosome pathway.