Loss of dopaminergic nigrostriatal neurons and fibrillary α-synuclein (α-syn) aggregation in Lewy bodies (LB) characterize Parkinson's disease (PD). We recently found that Synapsin III (Syn III), a phosphoprotein regulating dopamine (DA) release with α-syn, is another key component of LB fibrils in the brain of PD patients and acts as a crucial mediator of α-syn aggregation and toxicity. Methylphenidate (MPH), a monoamine reuptake inhibitor (MRI) efficiently counteracting freezing of gait in advanced PD patients, can bind α-syn and controls α-syn-mediated DA overflow and presynaptic compartmentalization. Interestingly, MPH results also efficient for the treatment of attention deficits and hyperactivity disorder (ADHD), a neurodevelopmental psychiatric syndrome associated with Syn III and α-syn polymorphisms and constituting a risk factor for the development of LB disorders. Here, we studied α-syn/Syn III co-deposition and longitudinal changes of α-syn, Syn III and DA transporter (DAT) striatal levels in nigrostriatal neurons of a PD model, the human C-terminally truncated (1-120) α-syn transgenic (SYN120 tg) mouse, in comparison with C57BL/6J wild type (wt) and C57BL/6JOlaHsd α-syn null littermates. Then, we analyzed the locomotor response of these animals to an acute administration of MPH (d-threo) and other MRIs: cocaine, that we previously found to stimulate Syn III-reliant DA release in the absence of α-syn, or the selective DAT blocker GBR-12935, along aging. Finally, we assessed whether these drugs modulate α-syn/Syn III interaction by fluorescence resonance energy transfer (FRET) and performed in silico studies engendering a heuristic model of the α-syn conformations stabilized upon MPH binding. We found that only MPH was able to over-stimulate a Syn III-dependent/DAT-independent locomotor activity in the aged SYN120 tg mice showing α-syn/Syn III co-aggregates. MPH enhanced full length (fl) α-syn/Syn III and even more (1-120) α-syn/Syn III interaction in cells exhibiting α-syn/Syn III inclusions. Moreover, in silico studies confirmed that MPH may reduce α-syn fibrillation by stabilizing a protein conformation with increased lipid binding predisposition. Our observations indicate that the motor-stimulating effect of MPH can be positively fostered in the presence of α-syn/Syn III co-aggregation. This evidence holds significant implications for PD and ADHD therapeutic management.

中文翻译：

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α-突触核蛋白/突触核蛋白III病理相互作用增强了对哌醋甲酯的运动反应。

路易体（LB）中多巴胺能黑质纹状体神经元的丢失和纤维状α-突触核蛋白（α-syn）聚集是帕金森氏病（PD）的特征。我们最近发现Synapsin III（Syn III）是一种与α-syn一起调节多巴胺（DA）释放的磷蛋白，是PD患者大脑中LB原纤维的另一个关键成分，并且是α-syn聚集和毒性的关键介质。 。哌醋甲酯（MPH）是一种单胺再摄取抑制剂（MRI），可有效抵抗晚期PD患者的步态冻结，可与α-syn结合并控制α-syn介导的DA溢出和突触前区室化。有趣的是，MPH结果对治疗注意力缺陷和多动症（ADHD）也很有效，与Syn III和α-syn多态性相关的神经发育性精神病综合症，构成LB疾病发展的危险因素。在这里，我们研究了PD模型的黑纹状体神经元中α-syn，Syn III和DA转运蛋白（DAT）纹状体水平的α-syn/ Syn III共沉积和纵向变化，人类C末端被截断了（1-120）与C57BL / 6J野生型（wt）和C57BL / 6JOlaHsdα-syn无效的同窝仔相比，α-syn转基因（SYN120 tg）小鼠。然后，我们分析了这些动物对MPH（d-threo）急性给药和其他MRI：可卡因的运动反应，可卡因是我们先前发现在不存在α-syn或选择性的情况下能刺激Syn III依赖的DA释放。 DAT阻滞剂GBR-12935，随着时间的流逝。最后，我们评估了这些药物是否通过荧光共振能量转移（FRET）调节了α-syn/ Syn III的相互作用，并进行了计算机模拟研究，得出了一种启发式的MPH结合稳定的α-syn构象模型。我们发现，只有MPH能够在显示α-syn/ Syn III共聚集的老年SYN120 tg小鼠中过度刺激Syn III依赖/ DAT独立的自发活动。在表现出α-syn/ Syn III内含物的细胞中，MPH增强了全长（fl）α-syn/ Syn III甚至更多（1-120）α-syn/ Syn III的相互作用。此外，计算机研究证实，MPH可通过稳定具有增加的脂质结合倾向的蛋白质构象来减少α-syn原纤维形成。我们的观察结果表明，在存在α-syn/ Syn III共聚集的情况下，可以积极增强MPH的运动刺激作用。