Chambers Nicole Elaine, Lanza Kathryn, Bishop Christopher
Department of Psychology, Binghamton University, Binghamton, NY, United States.
Front Pharmacol. 2020 Jan 15;10:1494. doi: 10.3389/fphar.2019.01494. eCollection 2019.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by hypokinetic motor features; however, patients also display non-motor symptoms like sleep disorders. The standard treatment for PD is dopamine replacement with L-DOPA; however, symptoms including gait deficits and sleep disorders are unresponsive to L-DOPA. Notably, these symptoms have been linked to aberrant activity in the pedunculopontine nucleus (PPN). Of late, clinical trials involving PPN deep brain stimulation (DBS) have been employed to alleviate gait deficits. Although preclinical evidence implicating PPN cholinergic neurons in gait dysfunction was initially promising, DBS trials fell short of expected outcomes. One reason for the failure of DBS may be that the PPN is a heterogenous nucleus that consists of GABAergic, cholinergic, and glutamatergic neurons that project to a diverse array of brain structures. Second, DBS trials may have been unsuccessful because PPN neurons are susceptible to mitochondrial dysfunction, Lewy body pathology, and degeneration in PD. Therefore, pharmaceutical or gene-therapy strategies targeting specific PPN neuronal populations or projections could better alleviate intractable PD symptoms. Unfortunately, how PPN neuronal populations and their respective projections influence PD motor and non-motor symptoms remains enigmatic. Herein, we discuss normal cellular and neuroanatomical features of the PPN, the differential susceptibility of PPN neurons to PD-related insults, and we give an overview of literature suggesting a role for PPN neurons in motor and sleep deficits in PD. Finally, we identify future approaches directed towards the PPN for the treatment of PD motor and sleep symptoms.
帕金森病（PD）是一种以运动功能减退为特征的神经退行性疾病；然而，患者还会出现睡眠障碍等非运动症状。PD的标准治疗方法是用左旋多巴进行多巴胺替代治疗；然而，包括步态缺陷和睡眠障碍在内的症状对左旋多巴无反应。值得注意的是，这些症状与脚桥核（PPN）的异常活动有关。最近，涉及PPN深部脑刺激（DBS）的临床试验已被用于缓解步态缺陷。尽管最初有临床前证据表明PPN胆碱能神经元与步态功能障碍有关，这很有前景，但DBS试验并未达到预期效果。DBS失败的一个原因可能是PPN是一个异质性核，由投射到多种脑结构的GABA能、胆碱能和谷氨酸能神经元组成。其次，DBS试验可能未成功是因为PPN神经元易受PD中线粒体功能障碍、路易体病理和变性的影响。因此，针对特定PPN神经元群体或投射的药物或基因治疗策略可能能更好地缓解难治性PD症状。不幸的是，PPN神经元群体及其各自的投射如何影响PD的运动和非运动症状仍然是个谜。在此，我们讨论PPN的正常细胞和神经解剖学特征、PPN神经元对PD相关损伤的不同易感性，并概述表明PPN神经元在PD运动和睡眠缺陷中起作用的文献。最后，我们确定未来针对PPN治疗PD运动和睡眠症状的方法。
