α-Synuclein Dimers Impair Vesicle Fission during Clathrin-Mediated Synaptic Vesicle Recycling.
α-Synuclein Dimers Impair Vesicle Fission during Clathrin-Mediated Synaptic Vesicle Recycling.
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DOI：
10.3389/fncel.2017.00388
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发表时间：
2017
影响因子：
5.3
通讯作者：
Morgan JR
中科院分区：
文献类型：
--
作者：
Medeiros AT;Soll LG;Tessari I;Bubacco L;Morgan JR
α-突触核蛋白是调节突触囊泡（SV）运输的突触前蛋白。在帕金森病（PD）和其他一些神经退行性疾病中，α-突触核蛋白的异常寡聚化和聚集导致突触功能障碍和神经毒性。尽管有证据表明α-突触核蛋白低聚物是在生理条件下在神经元内产生的，并且改变单体和低聚物的平衡有助于疾病的发病机制，但α-突触核蛋白的每种分子物种如何影响SV运输目前尚不清楚。为了解决这个问题，我们利用了七鳃鳗巨型网状脊髓（RS）突触的优势，这些突触可以通过轴突显微注射重组蛋白来进行急性扰动。我们之前报道了急性引入单体α-突触核蛋白抑制SV循环，包括对网格蛋白途径的影响。在这里，我们报道了α-突触核蛋白二聚体在突触中的作用。与单体α-突触核蛋白类似，两种重组α-突触核蛋白二聚体在体外与含有阴离子脂质的小脂质体结合，但效果降低。当引入突触时，α-突触核蛋白二聚体也会引起SV再循环缺陷，其中包括网格蛋白包覆的凹坑（ccp）的建立，其颈部狭窄，仍然附着在质膜上，这是一种表明囊泡裂变缺陷的表型。有趣的是，这两种α-突触核蛋白二聚体都诱导CCPs上的颈变长，以及复杂的分枝膜小管，这与动力蛋白抑制剂Dynasore诱导的CCPs不同。相反，单体α-突触核蛋白诱导自由网格蛋白包被囊泡（CCVs）的形成，表明在网格蛋白脱包过程的后期抑制了网格蛋白介导的内吞作用。综上所述，这些数据进一步支持过量α-突触核蛋白损害SV循环的结论。这些数据还表明，单体和二聚体α-突触核蛋白对网格蛋白介导的内吞作用有不同的影响，预示着不同的分子机制。了解这些机制可能有助于进一步阐明该蛋白的正常功能，以及PD病理的潜在机制。
α-Synuclein is a presynaptic protein that regulates synaptic vesicle (SV) trafficking. In Parkinson’s disease (PD) and several other neurodegenerative disorders, aberrant oligomerization and aggregation of α-synuclein lead to synaptic dysfunction and neurotoxicity. Despite evidence that α-synuclein oligomers are generated within neurons under physiological conditions, and that altering the balance of monomers and oligomers contributes to disease pathogenesis, how each molecular species of α-synuclein impacts SV trafficking is currently unknown. To address this, we have taken advantage of lamprey giant reticulospinal (RS) synapses, which are accessible to acute perturbations via axonal microinjection of recombinant proteins. We previously reported that acute introduction of monomeric α-synuclein inhibited SV recycling, including effects on the clathrin pathway. Here, we report the effects of α-synuclein dimers at synapses. Similar to monomeric α-synuclein, both recombinant α-synuclein dimers that were evaluated bound to small liposomes containing anionic lipids in vitro, but with reduced efficacy. When introduced to synapses, the α-synuclein dimers also induced SV recycling defects, which included a build up of clathrin-coated pits (CCPs) with constricted necks that were still attached to the plasma membrane, a phenotype indicative of a vesicle fission defect. Interestingly, both α-synuclein dimers induced longer necks on CCPs as well as complex, branching membrane tubules, which were distinct from the CCPs induced by a dynamin inhibitor, Dynasore. In contrast, monomeric α-synuclein induced a buildup of free clathrin-coated vesicles (CCVs), indicating an inhibition of clathrin-mediated endocytosis at a later stage during the clathrin uncoating process. Taken together, these data further support the conclusion that excess α-synuclein impairs SV recycling. The data additionally reveal that monomeric and dimeric α-synuclein produce distinct effects on clathrin-mediated endocytosis, predicting different molecular mechanisms. Understanding what these mechanisms are could help to further elucidate the normal functions of this protein, as well as the mechanisms underlying PD pathologies.
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影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1083/jcb.200212140
发表时间：
2003-05-26
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bloom O;Evergren E;Tomilin N;Kjaerulff O;Löw P;Brodin L;Pieribone VA;Greengard P;Shupliakov O
通讯作者：
Shupliakov O
影响因子：
34.7
作者：
Irwin, David J.;Lee, Virginia M. -Y.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
16.2
作者：
Bendor JT;Logan TP;Edwards RH
通讯作者：
Edwards RH
影响因子：
5.3
作者：
Burre, Jacqueline;Sharma, Manu;Suedhof, Thomas C.
通讯作者：
Suedhof, Thomas C.