The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome.
The ER retention protein RER1 promotes alpha-synuclein degradation via the proteasome.
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DOI：
10.1371/journal.pone.0184262
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
McFarland NR
中科院分区：
文献类型：
--
作者：
Park HJ;Ryu D;Parmar M;Giasson BI;McFarland NR
α-突触核蛋白（αSyn）的异常蓄积与内质网（ER）应激、细胞内蛋白/囊泡运输缺陷和细胞毒性有关。因此，参与ER相关蛋白加工和运输的靶向因子可能是调节αSyn水平和相关毒性的关键。最近，内质网滞留1（RER 1）已被确定为阿尔茨海默病蛋白的重要ER回收/滞留因子，并负调节淀粉样蛋白-β肽水平。在这里，我们假设RER 1也可能在αSyn的保留/检索中发挥重要作用，并介导水平。我们在HEK 293和H4神经胶质瘤细胞中表达了RER 1和缺乏ER保留/检索功能的C末端突变体RER 1 Δ25。RER 1过表达显着降低了αSyn野生型和A30 P、A53 T和E46 K疾病致病突变体的水平，而RER 1 Δ25突变体对αSyn具有显着减弱的作用。RER 1效应对αSyn具有特异性，对βSyn或Δ71-82 αSyn突变体几乎没有影响，这两种突变体都缺乏对突触核蛋白固定至关重要的NAC结构域序列。蛋白酶体和大自噬抑制剂的试验进一步证明，RER 1对αSyn的作用主要通过泛素-蛋白酶体系统介导。RER 1似乎也与泛素连接酶NEDD 4相互作用。人类患病脑组织中的RER 1与αSyn-positive Lewy bodies共定位。总之，这些发现提供了证据，证明RER 1是αSyn水平升高的一种新的和潜在的重要介质。进一步研究RER 1和αSyn下游效应物的机制可能会为帕金森病和相关突触核蛋白病的调节提供新的治疗靶点。
Abnormal accumulation of α-synuclein (αSyn) has been linked to endoplasmic-reticulum (ER) stress, defective intracellular protein/vesicle trafficking, and cytotoxicity. Targeting factors involved in ER-related protein processing and trafficking may, therefore, be a key to modulating αSyn levels and associated toxicity. Recently retention in endoplasmic reticulum 1 (RER1) has been identified as an important ER retrieval/retention factor for Alzheimer’s disease proteins and negatively regulates amyloid-β peptide levels. Here, we hypothesized that RER1 might also play an important role in retention/retrieval of αSyn and mediate levels. We expressed RER1 and a C-terminal mutant RER1Δ25, which lacks the ER retention/retrieval function, in HEK293 and H4 neuroglioma cells. RER1 overexpression significantly decreased levels of both wild type and A30P, A53T, and E46K disease causal mutants of αSyn, whereas the RER1Δ25 mutant had a significantly attenuated effect on αSyn. RER1 effects were specific to αSyn and had little to no effect on either βSyn or the Δ71–82 αSyn mutant, which both lack the NAC domain sequence critical for synuclein fibrillization. Tests with proteasomal and macroautophagy inhibitors further demonstrate that RER1 effects on αSyn are primarily mediated through the ubiquitin-proteasome system. RER1 also appears to interact with the ubiquitin ligase NEDD4. RER1 in human diseased brain tissues co-localizes with αSyn-positive Lewy bodies. Together, these findings provide evidence that RER1 is a novel and potential important mediator of elevated αSyn levels. Further investigation of the mechanism of RER1 and downstream effectors on αSyn may yield novel therapeutic targets for modulation in Parkinson disease and related synucleinopathies.
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DOI：
10.1073/pnas.89.6.2252
发表时间：
1992-03-15
影响因子：
11.1
作者：
CAPORASO, GL;GANDY, SE;GREENGARD, P
通讯作者：
GREENGARD, P
DOI：
10.1073/pnas.0912193106
发表时间：
2009-12-29
影响因子：
11.1
作者：
Chung, Chee Yeun;Koprich, James B.;Isacson, Ole
通讯作者：
Isacson, Ole
DOI：
10.1523/jneurosci.5367-11.2012
发表时间：
2012-03-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Colla E;Coune P;Liu Y;Pletnikova O;Troncoso JC;Iwatsubo T;Schneider BL;Lee MK
通讯作者：
Lee MK
影响因子：
56.9
作者：
Auluck, PK;Chan, HYE;Bonini, NM
通讯作者：
Bonini, NM
DOI：
10.1523/jneurosci.5368-11.2012
发表时间：
2012-03-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Colla E;Jensen PH;Pletnikova O;Troncoso JC;Glabe C;Lee MK
通讯作者：
Lee MK