A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes
A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes
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DOI：
10.1523/jneurosci.0344-18.2018
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发表时间：
2018-11-07
影响因子：
5.3
通讯作者：
Liao, Dezhi
中科院分区：
文献类型：
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作者：
Teravskis, Peter J.;Covelo, Ana;Liao, Dezhi
α-突触核蛋白的缺失与帕金森病（PD）的发病机制有关。由于α-突触核蛋白高度集中在突触前末梢内，因此突触前功能障碍已被提出为潜在的致病机制。在这里，我们报告了新的，tau依赖性，突触后缺陷引起的A53 T突变体α-突触核蛋白，这是与家族性PD。我们分析了表达人WT、A53 T和A30 P α-突触核蛋白的转基因小鼠的海马切片和培养的海马神经元中的突触活性。增加α-突触核蛋白表达导致减少自发突触囊泡释放，无论基因型。然而，只有那些表达A53 T α-突触核蛋白的神经元表现出突触后功能障碍，包括微小突触后电流幅度降低和AMPA与NMDA受体电流比率降低。我们还发现，长时程增强和空间学习受损的A53 T α-突触核蛋白的表达。从机制上讲，突触后功能障碍需要糖原合成酶激酶3 β介导的tau磷酸化、tau错误定位于树突棘和钙调神经磷酸酶依赖性AMPA受体内化。先前的研究表明，人类A53 T α-突触核蛋白具有高聚集潜力，这可以解释突变诱导突触后缺陷的独特能力。然而，伴有严重tau病理的散发性PD患者也更有可能出现早发性认知能力下降。我们的研究结果显示了tau蛋白的一种新的功能性作用：介导α-突触核蛋白对突触后信号的影响。因此，解开tau介导的信号级联可能有助于A53 T α-突触核蛋白连锁家族性PD病例中痴呆的发病机制，以及具有广泛tau病理的PD病例的一些亚组。
Abnormalities in alpha-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). Because alpha-synuclein is highly concentrated within presynaptic terminals, presynaptic dysfunction has been proposed as a potential pathogenic mechanism. Here, we report novel, tau-dependent, postsynaptic deficits caused by A53T mutant alpha-synuclein, which is linked to familial PD. We analyzed synaptic activity in hippocampal slices and cultured hippocampal neurons from transgenic mice of either sex expressing human WT, A53T, and A30P alpha-synuclein. Increased alpha-synuclein expression leads to decreased spontaneous synaptic vesicle release regardless of genotype. However, only those neurons expressing A53T alpha-synuclein exhibit postsynaptic dysfunction, including decreased miniature postsynaptic current amplitude and decreased AMPA to NMDA receptor current ratio. We also found that long-term potentiation and spatial learning were impaired by A53T alpha-synuclein expression. Mechanistically, postsynaptic dysfunction requires glycogen synthase kinase 3 beta-mediated tau phosphorylation, tau mislocalization to dendritic spines, and calcineurin-dependent AMPA receptor internalization. Previous studies reveal that human A53T alpha-synuclein has a high aggregation potential, which may explain the mutation's unique capacity to induce postsynaptic deficits. However, patients with sporadic PD with severe tau pathology are also more likely to have early onset cognitive decline. Our results here show a novel, functional role for tau: mediating the effects of alpha-synuclein on postsynaptic signaling. Therefore, the unraveled tau-mediated signaling cascade may contribute to the pathogenesis of dementia in A53T alpha-synuclein-linked familial PD cases, as well as some subgroups of PD cases with extensive tau pathology.