α-synuclein induced synapse damage is enhanced by amyloid-β1-42.
α-synuclein induced synapse damage is enhanced by amyloid-β1-42.
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DOI：
10.1186/1750-1326-5-55
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发表时间：
2010-12-07
影响因子：
15.1
通讯作者：
Williams A
中科院分区：
文献类型：
--
作者：
Bate C;Gentleman S;Williams A
帕金森病（PD）和路易体痴呆（DLB）的发病机制与α-突触核蛋白（αSN）蛋白聚集形式的积累有关。PD和DLB的神经病理学中的早期事件是突触的损失和突触蛋白水平的相应降低。然而，这些疾病中突触损伤的分子机制知之甚少。在这项研究中，突触损伤的过程是通过测量突触素的量来研究的，突触素是神经传递所必需的突触前膜蛋白，在与αSN或淀粉样蛋白-β（Aβ）肽孵育的培养神经元中，淀粉样蛋白-β（Aβ）肽被认为会引发阿尔茨海默病中的突触变性。我们报告，添加重组人αSN减少了培养的皮质和海马神经元中突触素的量，表明突触损伤。αSN还减少了突触囊泡的再循环，通过荧光染料FM 1 -43的摄取来测量。αSN对突触的这些作用通过与其他蛋白质的相互作用而改变。因此，βSN的加入降低了αSN对突触的影响。相反，加入淀粉样蛋白-β（Aβ）1-42加重了αSN对突触囊泡再循环和突触损伤的影响。同样，添加αSN增加了Aβ1-42诱导的突触损伤。然而，αSN的这种作用是选择性的，因为它不影响朊病毒衍生肽PrP 82 -146诱导的突触损伤。这些结果与αSN寡聚体触发帕金森病患者脑中突触损伤的假设一致。此外，他们认为αSN对突触的影响可能受到与大脑内产生的其他肽的相互作用的影响。
The pathogenesis of Parkinson's disease (PD) and dementia with Lewy bodies (DLB) is associated with the accumulation of aggregated forms of the α-synuclein (αSN) protein. An early event in the neuropathology of PD and DLB is the loss of synapses and a corresponding reduction in the level of synaptic proteins. However, the molecular mechanisms involved in synapse damage in these diseases are poorly understood. In this study the process of synapse damage was investigated by measuring the amount of synaptophysin, a pre-synaptic membrane protein essential for neurotransmission, in cultured neurons incubated with αSN, or with amyloid-β (Aβ) peptides that are thought to trigger synapse degeneration in Alzheimer's disease. We report that the addition of recombinant human αSN reduced the amount of synaptophysin in cultured cortical and hippocampal neurons indicative of synapse damage. αSN also reduced synaptic vesicle recycling, as measured by the uptake of the fluorescent dye FM1-43. These effects of αSN on synapses were modified by interactions with other proteins. Thus, the addition of βSN reduced the effects of αSN on synapses. In contrast, the addition of amyloid-β (Aβ)1-42 exacerbated the effects of αSN on synaptic vesicle recycling and synapse damage. Similarly, the addition of αSN increased synapse damage induced by Aβ1-42. However, this effect of αSN was selective as it did not affect synapse damage induced by the prion-derived peptide PrP82-146. These results are consistent with the hypothesis that oligomers of αSN trigger synapse damage in the brains of Parkinson's disease patients. Moreover, they suggest that the effect of αSN on synapses may be influenced by interactions with other peptides produced within the brain.
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