Leiden University and Leiden University Medical Center, Leiden, The Netherlands.
Netherlands Institute for Brain Research, Royal Academy of Arts and Sciences, Amsterdam, The Netherlands.
Med Princ Pract. 2023;32(3):155-165. doi: 10.1159/000531422. Epub 2023 Jun 7.
In 2020, more than 9 million patients suffering from Parkinson's disease (PD) were reported worldwide, and studies predict that the burden of this disease will grow substantially in industrial countries. In the last decade, there has been a better understanding of this neurodegenerative disorder, clinically characterized by motor disturbances, impaired balance, coordination, memory difficulties, and behavioral changes. Various preclinical investigations and studies on human postmortem brains suggest that local oxidative stress and inflammation promote misfolding and aggregation of alpha-synuclein within Lewy bodies and cause nerve cell damage. Parallel to these investigations, the familial contribution to the disease became evident from studies on genome-wide association in which specific genetic defects were linked to neuritic alpha-synuclein pathology. As for treatment, currently available pharmacological and surgical interventions may improve the quality of life but do not stop the progress of neurodegeneration. However, numerous preclinical studies have provided insights into the pathogenesis of PD. Their results provide a solid base for clinical trials and further developments. In this review, we discuss the pathogenesis, the prospects, and challenges of synolytic therapy, CRISPR, gene editing, and gene- and cell-based therapy. We also throw light on the recent observation that targeted physiotherapy may help improve the gait and other motor impairments.
2020 年，全球报告的帕金森病（PD）患者超过 900 万，研究预测，这种疾病在工业化国家的负担将大幅增加。在过去的十年中，人们对这种神经退行性疾病有了更好的理解，其临床特征是运动障碍、平衡、协调受损、记忆力困难和行为改变。各种临床前研究和对人类死后大脑的研究表明，局部氧化应激和炎症会促进α-突触核蛋白在路易小体中的错误折叠和聚集，并导致神经细胞损伤。与这些研究平行的是，对全基因组关联的研究表明，特定的遗传缺陷与神经突α-突触核蛋白病理学有关，从而证明了家族对疾病的贡献。至于治疗，目前可用的药物和手术干预措施可能会提高生活质量，但无法阻止神经退行性变的进展。然而，大量的临床前研究为 PD 的发病机制提供了深入的了解。其结果为临床试验和进一步发展提供了坚实的基础。在这篇综述中，我们讨论了溶酶体治疗、CRISPR、基因编辑和基于基因和细胞的治疗的发病机制、前景和挑战。我们还强调了最近的观察结果，即有针对性的物理疗法可能有助于改善步态和其他运动障碍。
