L-DOPA Impairs Proteasome Activity in Parkinsonism through D1 Dopamine Receptor
L-DOPA Impairs Proteasome Activity in Parkinsonism through D1 Dopamine Receptor
复制标题
DOI：
10.1523/jneurosci.1541-11.2012
复制
发表时间：
2012-01-11
影响因子：
5.3
通讯作者：
Martin-Negrier, Marie-Laure
中科院分区：
文献类型：
--
作者：
Berthet, Amandine;Bezard, Erwan;Martin-Negrier, Marie-Laure
多巴胺D-1受体（D1R）的异常膜定位与左旋多巴诱导的运动障碍（LID）有关，这是左旋多巴治疗帕金森病（PD）的主要并发症。由于蛋白酶体通过调节神经递质受体在神经元内的命运在调节神经元反应中起核心作用，我们假设泛素-蛋白酶体蛋白水解途径可能在LID中受损。在实验性的啮齿动物和猴子帕金森症中，这些眼皮实际上与纹状体特异性的蛋白酶体催化活性下降和多泛素化蛋白的积累有关。然后，我们证明了蛋白酶体催化活性的降低(1)是由D1R激活引起的，(2)是D1R异常运输的反馈，即其夸大的细胞表面丰度。我们进一步发现，与野生型小鼠相比，E3泛素蛋白连接酶parkin PD基因的遗传失活导致异常不自主运动的夸大。因此，我们在一系列前所未有的实验模型中建立了泛素-蛋白酶体系统在特定节点（E3连接酶帕金，多泛素化，蛋白酶体催化活性）的损伤导致相同的现象，即PD患者对多巴胺替代治疗的异常行为反应，突出了在非退行性背景下多巴胺受体和蛋白酶体活性之间的密切相互作用。
Aberrant membrane localization of dopamine D-1 receptor (D1R) is associated with L-DOPA-induced dyskinesia (LID), a major complication of L-DOPA treatment in Parkinson's disease (PD). Since the proteasome plays a central role in modulating neuronal response through regulation of neurotransmitter receptor intraneuronal fate, we hypothesized that the ubiquitine-proteasome proteolytic pathway could be impaired in LID. Those LIDs are actually associated with a striatum-specific decrease in proteasome catalytic activity and accumulation of polyubiquitinated proteins in experimental rodent and monkey parkinsonism. We then demonstrated that such decreased proteasome catalytic activity (1) results from D1R activation and (2) feed-back the D1R abnormal trafficking, i.e., its exaggerated cell surface abundance. We further showed that the genetic invalidation of the E3 ubiquitin-protein ligase parkin PD gene leads to exaggerated abnormal involuntary movements compared with wild-type mice. We thus established in an unprecedented series of experimental models that impairment of the ubiquitine-proteasome system at specific nodes (E3 ligase parkin, polyubiquitination, proteasome catalytic activity) leads to the same phenomenon, i.e., aberrant behavioral response to dopamine replacement therapy in PD, highlighting the intimate interplay between dopamine receptor and proteasome activity in a nondegenerative context.