Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder.
Altered synaptobrevin-II trafficking in neurons expressing a synaptophysin mutation associated with a severe neurodevelopmental disorder.
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DOI：
10.1016/j.nbd.2017.08.021
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发表时间：
2017-12
影响因子：
6.1
通讯作者：
Cousin MA
中科院分区：
文献类型：
--
作者：
Harper CB;Mancini GMS;van Slegtenhorst M;Cousin MA
胞吐作用后，突触囊泡（SV）必须以正确的化学计量用正确的蛋白质补充来重组，以确保持续的神经传递。突触泡蛋白是一种高度丰富的、完整的SV蛋白，其对于SV SNARE蛋白、小突触泡蛋白II（synaptobrevin II，syb II）的有效恢复是必需的。然而，突触体蛋白依赖的syb II检索的分子机制仍然不清楚。我们最近发现了一个男性患者，患有严重的智力残疾，肌张力减退，癫痫和胼胝体发育不全谁有一个点突变的突触素（T198I）的第四跨膜结构域的质膜区域。该突变对突触体蛋白的活性依赖性检索没有影响，该突触体蛋白在突触体蛋白敲除海马培养物中用遗传编码的pH敏感性报告基因（pHluorin）标记。这表明突变体对SV内吞作用没有全局影响，这在检查不同SV货物（谷氨酸转运蛋白vGLUT 1）的回收时得到证实。然而，表达这种T198I突变体的神经元确实显示受损的活动依赖性sybII检索，类似于在突触体蛋白敲除神经元中观察到的。有趣的是，这种损伤并没有导致sybII在质膜上的搁浅增加。筛选已知的人类突触素突变揭示了T198I和X连锁智力残疾中发现的突变之间相似的突触前表型。因此，这种新的人类突触素突变揭示了SV货物的异常回收和增加的质膜定位可以在人类疾病中解耦。在人类疾病中发现了一种新的突触素变体。该突变选择性干扰活性依赖性小突触素II检索。它揭示了质膜表达可以与囊泡货物回收分离。
Following exocytosis, synaptic vesicles (SVs) have to be reformed with the correct complement of proteins in the correct stoichiometry to ensure continued neurotransmission. Synaptophysin is a highly abundant, integral SV protein necessary for the efficient retrieval of the SV SNARE protein, synaptobrevin II (sybII). However the molecular mechanism underpinning synaptophysin-dependent sybII retrieval is still unclear. We recently identified a male patient with severe intellectual disability, hypotonia, epilepsy and callosal agenesis who has a point mutation in the juxtamembrane region of the fourth transmembrane domain of synaptophysin (T198I). This mutation had no effect on the activity-dependent retrieval of synaptophysin that was tagged with the genetically-encoded pH-sensitive reporter (pHluorin) in synaptophysin knockout hippocampal cultures. This suggested the mutant has no global effect on SV endocytosis, which was confirmed when retrieval of a different SV cargo (the glutamate transporter vGLUT1) was examined. However neurons expressing this T198I mutant did display impaired activity-dependent sybII retrieval, similar to that observed in synaptophysin knockout neurons. Interestingly this impairment did not result in an increased stranding of sybII at the plasma membrane. Screening of known human synaptophysin mutations revealed a similar presynaptic phenotype between T198I and a mutation found in X-linked intellectual disability. Thus this novel human synaptophysin mutation has revealed that aberrant retrieval and increased plasma membrane localisation of SV cargo can be decoupled in human disease. A novel synaptophysin variant has been identified in human disease. The mutation selectively perturbs activity-dependent synaptobrevin II retrieval. It reveals plasma membrane expression can be decoupled from vesicle cargo retrieval.
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影响因子：
3.3
作者：
Felkl, M.;Leube, R. E.
通讯作者：
Leube, R. E.
影响因子：
5.3
作者：
Atluri, PP;Ryan, TA
通讯作者：
Ryan, TA
影响因子：
11.4
作者：
EDELMANN, L;HANSON, PI;JAHN, R
通讯作者：
JAHN, R
DOI：
10.1073/pnas.1218432110
发表时间：
2013-02-05
影响因子：
11.1
作者：
Kononenko, Natalia L.;Diril, M. Kasim;Haucke, Volker
通讯作者：
Haucke, Volker
影响因子：
3.5
作者：
Corradi A;Fadda M;Piton A;Patry L;Marte A;Rossi P;Cadieux-Dion M;Gauthier J;Lapointe L;Mottron L;Valtorta F;Rouleau GA;Fassio A;Benfenati F;Cossette P
通讯作者：
Cossette P