Sassone Jenny, Valtorta Flavia, Ciammola Andrea
Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Vita-Salute San Raffaele University, Milan, Italy.
Front Neurosci. 2019 Mar 26;13:273. doi: 10.3389/fnins.2019.00273. eCollection 2019.
Mutations in the gene cause early-onset Parkinson's disease (PD). Despite the high proportion of still missing phenotyping data in the literature devoted to early-onset PD, studies suggest that, as compared with late-onset PD, patients show dystonia at onset and extremely dose-sensitive levodopa-induced dyskinesia (LID). What pathophysiological mechanisms underpin such early and atypical dyskinesia in patients with mutations? Though the precise mechanisms underlying dystonia and LID are still unclear, evidence suggests that hyperkinetic disorders in PD are a behavioral expression of maladaptive functional and morphological changes at corticostriatal synapses induced by long-term dopamine (DA) depletion. However, since the dyskinesia in patients can also be present at onset, other mechanisms beside the well-established DA depletion may play a role in the development of dyskinesia in these patients. Because cortical and striatal neurons express parkin protein, and parkin modulates the function of ionotropic glutamatergic receptors (iGluRs), an intriguing explanation may rest on the potential role of parkin in directly controlling the glutamatergic corticostriatal synapse transmission. We discuss the novel theory that loss of parkin function can dysregulate transmission at the corticostriatal synapses where they cause early maladaptive changes that co-occur with the changes stemming from DA loss. This hypothesis suggests an early striatal synaptopathy; it could lay the groundwork for pharmacological treatment of dyskinesias and LID in patients with mutations.
该基因的突变会导致早发性帕金森病（PD）。尽管在有关早发性PD的文献中仍有很大比例的表型数据缺失，但研究表明，与晚发性PD相比，该基因突变患者在发病时会出现肌张力障碍以及对左旋多巴诱导的异动症（LID）极为敏感。在该基因突变患者中，何种病理生理机制导致了这种早期和非典型的异动症？尽管肌张力障碍和LID的确切机制仍不清楚，但有证据表明，PD中的运动亢进障碍是长期多巴胺（DA）耗竭诱导的皮质纹状体突触处适应性功能和形态变化的行为表现。然而，由于该基因突变患者的异动症在发病时也可能出现，因此除了已明确的DA耗竭之外，其他机制可能也在这些患者异动症的发生中起作用。由于皮质和纹状体神经元表达帕金蛋白，且帕金调节离子型谷氨酸能受体（iGluRs）的功能，一个有趣的解释可能基于帕金在直接控制谷氨酸能皮质纹状体突触传递中的潜在作用。我们讨论了一种新理论，即帕金功能丧失会导致皮质纹状体突触处的传递失调，在这些突触处会引起早期适应性不良变化，这些变化与DA丧失所导致的变化同时出现。这一假说提示了早期纹状体突触病变；它可能为该基因突变患者的异动症和LID的药物治疗奠定基础。
