Parkinson's disease: etiopathogenesis and treatment
Parkinson's disease: etiopathogenesis and treatment
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帕金森病的发病机制和治疗
DOI：
10.1136/jnnp-2019-322338
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发表时间：
2020-08-01
影响因子：
11
通讯作者：
Tan, Eng King
中科院分区：
文献类型：
--
作者：
Jankovic, Joseph;Tan, Eng King
“特发性”帕金森病 (PD) 作为单一实体的概念受到了多种临床亚型、致病基因和假定致病环境因素的挑战。除了典型的运动症状外，非运动症状（如快速动眼睡眠障碍、嗅觉丧失、便秘和抑郁）出现在前驱/运动前阶段，并随着疾病的进展而出现认知障碍和自主神经功能障碍，通常主导疾病的晚期阶段。关键的分子致病机制包括α-突触核蛋白错误折叠和聚集、线粒体功能障碍、蛋白质清除受损（与泛素蛋白酶体和自噬溶酶体系统缺陷相关）、神经炎症和氧化应激。多巴胺能以及去甲肾上腺素能、谷氨酸能、血清素能和腺苷途径的参与提供了对与 PD 相关的丰富多变的临床现象学的见解，以及传统多巴胺替代疗法之外的替代治疗方法的可能性。开发潜在神经保护疗法的最大挑战之一是缺乏可靠和敏感的生物标志物 的进步。免疫疗法，例如使用针对聚集的有毒α-突触核蛋白的疫苗接种或单克隆抗体。以及抗聚集或蛋白质清除策略目前正在临床试验中进行研究。胰高血糖素样肽1受体激动剂、特定PD基因靶向药物（例如GBA或LRRK2修饰剂）和其他潜在的疾病修饰药物的应用使人们谨慎乐观地认为更有效的疗法即将出现。新兴疗法，如新的对症药物、创新的药物输送系统和新颖的手术干预措施，给帕金森病患者的未来结果和预后带来了希望。
The concept of 'idiopathic' Parkinson's disease (PD) as a single entity has been challenged with the identification of several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such as rapid eye movement sleep disorder, anosmia, constipation and depression) appear at prodromic/premotor stage and evolve, along with cognitive impairment and dysautonomia, as the disease progresses, often dominating the advanced stages of the disease. The key molecular pathogenic mechanisms include alpha-synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (associated with deficient ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. The involvement of dopaminergic as well as noradrenergic, glutamatergic, serotonergic and adenosine pathways provide insights into the rich and variable clinical phenomenology associated with PD and the possibility of alternative therapeutic approaches beyond traditional dopamine replacement therapies.One of the biggest challenges in the development of potential neuroprotective therapies has been the lack of reliable and sensitive biomarkers of progression. Immunotherapies such as the use of vaccination or monoclonal antibodies directed against aggregated, toxic alpha-synuclein. as well as anti-aggregation or protein clearance strategies are currently investigated in clinical trials. The application of glucagon-like peptide one receptor agonists, specific PD gene target agents (such as GBA or LRRK2 modifiers) and other potential disease modifying drugs provide cautious optimism that more effective therapies are on the horizon. Emerging therapies, such as new symptomatic drugs, innovative drug delivery systems and novel surgical interventions give hope to patients with PD about their future outcomes and prognosis.