Pruning and loss of excitatory synapses by the parkin ubiquitin ligase
Pruning and loss of excitatory synapses by the parkin ubiquitin ligase
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DOI：
10.1073/pnas.0802280105
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发表时间：
2008-12-09
影响因子：
11.1
通讯作者：
Ehlers, Michael D.
中科院分区：
文献类型：
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作者：
Helton, Thomas D.;Otsuka, Takeshi;Ehlers, Michael D.
PARK2基因突变导致遗传性帕金森病（PD）。PARK2基因产物，称为parkin，是一种E3泛素连接酶，介导泛素转移到不同的底物蛋白上。尽管在确定帕金的分子特性和底物方面取得了进展，但对其生理功能知之甚少。在这里，我们表明，帕金调节兴奋性突触的功能和稳定性。帕金的突触后表达抑制兴奋性突触传递并导致海马神经元上的兴奋性突触的显著损失。相反，内源性帕金蛋白的敲低或PD连锁帕金蛋白突变体的表达深刻地增强了突触功效，并触发了突触能突触的增殖。这种增殖与突触兴奋性毒性的脆弱性增加有关。因此，帕金负调节兴奋性突触的数量和强度。帕金森氏病的病理生理学机制可能与帕金森氏病的兴奋性冲动增加有关。
Mutations in the PARK2 gene cause hereditary Parkinson disease (PD). The PARK2 gene product, termed parkin, is an E3 ubiquitin ligase that mediates the transfer of ubiquitin onto diverse substrate proteins. Despite progress in defining the molecular properties and substrates of parkin, little is known about its physiological function. Here, we show that parkin regulates the function and stability of excitatory glutamatergic synapses. Postsynaptic expression of parkin dampens excitatory synaptic transmission and causes a marked loss of excitatory synapses onto hippocampal neurons. Conversely, knockdown of endogenous parkin or expression of PD-linked parkin mutants profoundly enhances synaptic efficacy and triggers a proliferation of glutamatergic synapses. This proliferation is associated with increased vulnerability to synaptic excitotoxicity. Thus, parkin negatively regulates the number and strength of excitatory synapses. Increased excitatory drive produced by disruption of parkin may contribute to the pathophysiology of PD.