Sezione di Neurologia, Dipartimento di Neuroscienze, Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, Rome, 00168, Italy.
Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy.
Brain. 2023 Sep 1;146(9):3587-3597. doi: 10.1093/brain/awad150.
The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments have not yet shown clear efficacy in slowing the progression of this disease. Several explanations exist for this issue. The pathogenesis of Parkinson's disease is complex and not yet fully clarified and the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity. Thus, a deep understanding of alpha-synuclein physiological and pathophysiological functions is crucial. In this review, we first describe the cellular and animal models developed over recent years to study the physiological and pathological roles of this protein, including transgenic techniques, use of viral vectors and intracerebral injections of alpha-synuclein fibrils. We then provide evidence that these tools are crucial for modelling Parkinson's disease pathogenesis, causing protein misfolding and aggregation, synaptic dysfunction, brain plasticity impairment and cell-to-cell spreading of alpha-synuclein species. In particular, we focus on the possibility of dissecting the pre- and postsynaptic effects of alpha-synuclein in both physiological and pathological conditions. Finally, we show how vulnerability of specific neuronal cell types may facilitate systemic dysfunctions leading to multiple network alterations. These functional alterations underlie diverse motor and non-motor manifestations of Parkinson's disease that occur before overt neurodegeneration. However, we now understand that therapeutic targeting of alpha-synuclein in Parkinson's disease patients requires caution, since this protein exerts important physiological synaptic functions. Moreover, the interactions of alpha-synuclein with other molecules may induce synergistic detrimental effects. Thus, targeting only alpha-synuclein might not be enough. Combined therapies should be considered in the future.
α-突触核蛋白在帕金森病中的关键作用是一个重要发现。近年来，在确定针对帕金森病的靶向α-突触核蛋白的疾病修饰治疗方法方面已经取得了一些进展。然而，这些治疗方法尚未显示出明显延缓该疾病进展的疗效。对此存在几种解释。帕金森病的发病机制复杂，尚未完全阐明，而且疾病的异质性，包括不同的遗传易感性和风险因素以及不同的临床病程，增加了更多的复杂性。因此，深入了解α-突触核蛋白的生理和病理生理学功能至关重要。在这篇综述中，我们首先描述了近年来为研究该蛋白的生理和病理作用而开发的细胞和动物模型，包括转基因技术、病毒载体的使用和α-突触核蛋白原纤维的脑内注射。然后我们提供了证据表明，这些工具对于模拟帕金森病的发病机制至关重要，导致蛋白质错误折叠和聚集、突触功能障碍、脑可塑性损伤以及α-突触核蛋白物种的细胞间传播。特别是，我们关注了在生理和病理条件下剖析α-突触核蛋白的前突触和后突触效应的可能性。最后，我们展示了特定神经元细胞类型的易感性如何促进导致多种网络改变的全身功能障碍。这些功能改变是帕金森病在明显神经退行性变之前出现的多种运动和非运动表现的基础。然而，我们现在了解到，在帕金森病患者中靶向治疗α-突触核蛋白需要谨慎，因为该蛋白发挥着重要的生理突触功能。此外，α-突触核蛋白与其他分子的相互作用可能会产生协同的有害影响。因此，仅靶向α-突触核蛋白可能还不够。未来应该考虑联合治疗。
