Grosso Jasutkar Hilary, Oh Stephanie E, Mouradian M Maral
Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, New Jersey.
Robert Wood Johnson Medical School Institute for Neurological Therapeutics, and Department of Neurology, Rutgers Biomedical and Health Sciences, Piscataway, New Jersey
Pharmacol Rev. 2022 Jan;74(1):207-237. doi: 10.1124/pharmrev.120.000133.
Parkinson's disease (PD) is the second most common neurodegenerative disorder and the fastest growing neurologic disease in the world, yet no disease-modifying therapy is available for this disabling condition. Multiple lines of evidence implicate the protein -synuclein (-Syn) in the pathogenesis of PD, and as such, there is intense interest in targeting -Syn for potential disease modification. -Syn is also a key pathogenic protein in other synucleionpathies, most commonly dementia with Lewy bodies. Thus, therapeutics targeting this protein will have utility in these disorders as well. Here we discuss the various approaches that are being investigated to prevent and mitigate -Syn toxicity in PD, including clearing its pathologic aggregates from the brain using immunization strategies, inhibiting its misfolding and aggregation, reducing its expression level, enhancing cellular clearance mechanisms, preventing its cell-to-cell transmission within the brain and perhaps from the periphery, and targeting other proteins associated with or implicated in PD that contribute to -Syn toxicity. We also discuss the therapeutics in the pipeline that harness these strategies. Finally, we discuss the challenges and opportunities for the field in the discovery and development of therapeutics for disease modification in PD. SIGNIFICANCE STATEMENT: PD is the second most common neurodegenerative disorder, for which disease-modifying therapies remain a major unmet need. A large body of evidence points to -synuclein as a key pathogenic protein in this disease as well as in dementia with Lewy bodies, making it of leading therapeutic interest. This review discusses the various approaches being investigated and progress made to date toward discovering and developing therapeutics that would slow and stop progression of these disabling diseases.
帕金森病（PD）是世界上第二常见的神经退行性疾病，也是增长最快的神经系统疾病，但目前尚无针对这种致残性疾病的疾病修饰疗法。多条证据表明，α-突触核蛋白（α-Syn）与帕金森病的发病机制有关，因此，针对α-Syn进行潜在疾病修饰的研究备受关注。α-Syn也是其他突触核蛋白病的关键致病蛋白，最常见的是路易体痴呆。因此，针对这种蛋白质的治疗方法在这些疾病中也将具有实用性。在这里，我们讨论了正在研究的各种预防和减轻帕金森病中α-Syn毒性的方法，包括使用免疫策略清除大脑中的病理性聚集体、抑制其错误折叠和聚集、降低其表达水平、增强细胞清除机制、防止其在大脑内以及可能从外周进行细胞间传播，以及针对与帕金森病相关或涉及导致α-Syn毒性的其他蛋白质。我们还讨论了采用这些策略的在研治疗方法。最后，我们讨论了该领域在发现和开发帕金森病疾病修饰疗法方面面临的挑战和机遇。意义声明：帕金森病是第二常见的神经退行性疾病，疾病修饰疗法仍然是一个主要未满足的需求。大量证据表明，α-突触核蛋白是这种疾病以及路易体痴呆的关键致病蛋白，使其成为主要的治疗研究对象。这篇综述讨论了正在研究的各种方法以及迄今为止在发现和开发能够减缓并阻止这些致残性疾病进展的治疗方法方面所取得的进展。
