Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark; Department of Biomedicine, Dandrite, Faculty of Health, Aarhus University, Aarhus, Denmark.
Department of Neurodegeneration, Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark.
Neurobiol Dis. 2018 Aug;116:13-27. doi: 10.1016/j.nbd.2018.04.011. Epub 2018 Apr 20.
Parkinson's disease (PD) affects motor function through degenerative processes and synaptic transmission impairments in the basal ganglia. None of the treatments available delays or stops the progression of the disease. While α-synuclein pathological accumulation represents a hallmark of the disease in its idiopathic form, leucine rich repeat kinase 2 (LRRK2) is genetically associated with familial and sporadic forms of PD. The genetic information suggests that LRRK2 kinase activity plays a role in the pathogenesis of the disease. To support a potential link between LRRK2 and α-synuclein in the pathophysiological mechanisms underlying PD, the effect of LRRK2 ablation or LRRK2 kinase pharmacological inhibition were studied in rats with adeno-associated virus-induced (AAV) α-synuclein overexpression in the nigrostriatal pathway. We first report that viral overexpression of α-synuclein induced increased burst firing in subthalamic neurons. Aberrant firing pattern of subthalamic neurons has also been reported in PD patients and neurotoxin-based animal models, and is hypothesized to play a key role in the appearance of motor dysfunction. We further report that genetic LRRK2 ablation, as well as pharmacological inhibition of LRRK2 kinase activity with PFE-360, reversed the aberrant firing pattern of subthalamic neurons induced by AAV-α-synuclein overexpression. This effect of LRRK2 modulation was not associated with any neuroprotective effect or motor improvement. Nonetheless, our findings may indicate a potential therapeutic benefit of LRRK2 kinase inhibition by normalizing the aberrant neuronal activity of subthalamic neurons induced by AAV-α-synuclein, a neurophysiological trait recapitulating observations in PD.
帕金森病（PD）通过基底神经节的退行性过程和突触传递损伤影响运动功能。目前尚无任何治疗方法可以延缓或阻止疾病的进展。虽然α-突触核蛋白病理性积累代表了特发性疾病的标志，但富含亮氨酸重复激酶 2（LRRK2）与家族性和散发性 PD 有关。遗传信息表明，LRRK2 激酶活性在疾病的发病机制中起作用。为了支持 LRRK2 和α-突触核蛋白在 PD 潜在的病理生理机制之间的联系，研究了腺相关病毒诱导（AAV）α-突触核蛋白在黑质纹状体通路中过表达的大鼠中 LRRK2 缺失或 LRRK2 激酶药理学抑制的作用。我们首先报告，α-突触核蛋白的病毒过表达诱导了丘脑下核神经元的爆发性放电增加。PD 患者和神经毒素动物模型也报道了丘脑下核神经元的异常放电模式，并且被假设在运动功能障碍的出现中发挥关键作用。我们进一步报告，LRRK2 的基因缺失，以及用 PFE-360 抑制 LRRK2 激酶活性，逆转了 AAV-α-突触核蛋白过表达诱导的丘脑下核神经元的异常放电模式。LRRK2 调节的这种作用与任何神经保护作用或运动改善无关。尽管如此，我们的发现可能表明通过正常化 AAV-α-突触核蛋白诱导的丘脑下核神经元的异常神经元活动，LRRK2 激酶抑制具有潜在的治疗益处，这是一种神经生理学特征，再现了 PD 中的观察结果。
