Neurodegenerative Disease Related Proteins Have Negative Effects on SNARE-Mediated Membrane Fusion in Pathological Confirmation.
Neurodegenerative Disease Related Proteins Have Negative Effects on SNARE-Mediated Membrane Fusion in Pathological Confirmation.
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神经退行性疾病相关蛋白在病理证实中对 SNARE 介导的膜融合有负面影响
DOI：
10.3389/fnmol.2017.00066
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发表时间：
2017
影响因子：
4.8
通讯作者：
Long J
中科院分区：
文献类型：
--
作者：
Hou C;Wang Y;Liu J;Wang C;Long J
研究表明，突触是突触前和突触后神经元之间通信的高度专门化结构（Kaeser和Regehr，2014）。携带神经递质的突触囊泡停靠在突触前膜的特定位点，称为活动区，其与突触后密度紧密并列，然后经历一个或多个引发反应以使其准备释放状态。当动作电位侵入神经末梢时，随后的膜去极化激活电压门控性钙通道，使Ca 2+内流，从而启动突触囊泡与突触前膜的融合和递质释放（Wu and Saggau，1997）。据报道，突触囊泡融合需要被称为可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）的保守蛋白质家族的组装（Chernomordik和Kozlov，2008; Wickner和Schekman，2008）。所有的SNARE都含有进化上保守的卷曲螺旋SNARE基序，其由大约60-70个氨基酸组成，以七肽重复序列排列。在突触中，质膜上的25 kDa突触融合蛋白和突触体相关蛋白（SNAP-25，含有两个SNARE基序）（靶膜上的t-SNARE）和突触囊泡上的小突触蛋白/囊泡相关膜蛋白（VAMP）（v-SNARE）以1：1：1的比例组装成紧密的反式SNARE复合物，以桥接突触囊泡和质膜（Brunger，2005）。反式SNARE复合物通过在其拉链拉上时将双层拉在一起来促进膜融合，并且融合膜上的剩余SNARE复合物转化为具有较低势能的顺式构型，其经历由专门的腺苷三磷酸酶（ATP酶）N-乙基马来酰亚胺敏感因子（NSF）及其辅因子可溶性NSF附着蛋白（SNAP）催化的分解（Jahn et al.，2003年）。SNAP直接与SNARE复合物结合，然后募集并激活NSF以完全解离SNARE复合物并回收单个SNARE用于新一轮融合反应（Sudhof和Rothman，2009）。因此，似乎SNARE组装和拆卸的周期对于突触传递的发生、保真度和可塑性至关重要。同时，研究表明，多种神经退行性疾病的特征在于神经元功能障碍和神经元损失，这是由特定神经毒性蛋白的聚集引起的（Caughey和Lansbury，2003）。通常，α-突触核蛋白（α-syn）构成路易体的淀粉样原纤维形式（Wang等人，2016），是由140个氨基酸残基组成的胞质神经蛋白，并且以单体形式在突触前膜中大量表达（Burre et al.，2013年）。α-syn与家族性帕金森病、阿尔茨海默病和路易体病等神经退行性疾病的早发密切相关。Aβ，一种肽...
Studies showed that synapses are highly-specialized structures for the communication between pre-and postsynaptic neurons (Kaeser and Regehr, 2014). Synaptic vesicles carrying neurotransmitters dock at specialized sites of presynaptic membranes termed active zones, which are closely apposed to postsynaptic densities, and then undergo one or more priming reactions to prepare them to a release-ready state. When an action potential invades the nerve terminals, the following membrane depolarization activates voltage-gated calcium channels to influx Ca 2+ , thus initiates the fusion of synaptic vesicles with presynaptic membrane and transmitters release (Wu and Saggau, 1997). It was reported that synaptic vesicle fusion requires assembly of a conserved proteins family termed soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (Chernomordik and Kozlov, 2008; Wickner and Schekman, 2008). All SNAREs contain an evolutionarily conserved coiled-coil SNARE motif of ∼60–70 amino acids that are arranged in heptad repeats. In synapses, syntaxin and synaptosome-associated protein of 25 kDa (SNAP-25, contains two SNARE motifs) on the plasma membrane (t-SNAREs on target membrane) and synaptobrevin/vesicle-associated membrane protein (VAMP) on synaptic vesicles (v-SNARE) assemble into a tight trans-SNARE complex in a 1:1:1 ratio to bridge synaptic vesicles and the plasma membrane (Brunger, 2005). The trans-SNARE complex promotes membrane fusion by pulling the bilayers together as it zippers up, and the remaining SNARE complexes on the fused membrane are transformed to cis-configuration with lower potential energy, which undergoes disassembly catalyzed by a specialized adenosine triphosphatase (ATPase) N-ethylmaleimide-sensitive factor (NSF) and its cofactors soluble NSF attachment proteins (SNAPs) (Jahn et al., 2003). SNAPs bind directly to the SNARE complex, then recruit and activate NSF to completely dissociate SNARE complex and recycle individual SNAREs for a new round of fusion reactions (Sudhof and Rothman, 2009). Thus, it appears that the cycle of SNARE assembly and disassembly is critical for the occurrence, the fidelity and plasticity of synaptic transmission. Meanwhile, it has been shown that a wide range of neurodegenerative disorders are characterized with neuronal dysfunction and neuron loss, which caused by the aggregation of specific neurotoxic proteins (Caughey and Lansbury, 2003). Typically, α-synuclein (α-syn), constitutes the amyloid fibril form of Lewy bodies (Wang et al., 2016), is a cytosolic neural protein consisting of 140 amino acid residues and is abundantly expressed in presynaptic membrane in monomeric form (Burre et al., 2013). α-syn is closely associated with early-onset of neurodegenerative diseases prominently in familial Parkinson's disease, Alzheimer's disease and Lewy body disease. Aβ, a peptide …