Advances in understanding the function of alpha-synuclein: implications for Parkinson's disease.
Advances in understanding the function of alpha-synuclein: implications for Parkinson's disease.
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了解α-突触核蛋白功能的进展：对帕金森病的影响
DOI：
10.1093/brain/awad150
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发表时间：
2023-09-01
期刊：
影响因子：
14.5
通讯作者：
Ghiglieri, Veronica
中科院分区：
文献类型：
--
作者：
Calabresi, Paolo;Di Lazzaro, Giulia;Marino, Gioia;Campanelli, Federica;Ghiglieri, Veronica
α-突触核蛋白在帕金森病中的关键作用代表了一个关键发现。近年来，在确定针对α-突触核蛋白的帕金森病的疾病修饰疗法方面取得了一些进展。然而，这些治疗在减缓这种疾病的进展方面尚未显示出明确的疗效。对这个问题有几种解释。帕金森病的发病机制是复杂的，尚未完全阐明，疾病的异质性，具有不同的遗传易感性和风险因素以及不同的临床病程，增加了进一步的复杂性。因此，深入了解α-突触核蛋白的生理和病理生理功能至关重要。在这篇综述中，我们首先描述了近年来开发的细胞和动物模型来研究这种蛋白质的生理和病理作用，包括转基因技术，使用病毒载体和脑内注射α-突触核蛋白纤维。然后，我们提供的证据表明，这些工具是至关重要的建模帕金森病的发病机制，导致蛋白质错误折叠和聚集，突触功能障碍，脑可塑性损伤和细胞间传播的α-突触核蛋白物种。特别是，我们专注于解剖前和突触后的影响，在生理和病理条件下的α-突触核蛋白的可能性。最后，我们展示了特定神经元细胞类型的脆弱性如何促进导致多种网络改变的系统功能障碍。这些功能改变是帕金森病在明显神经变性之前发生的各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α-突触核蛋白的治疗靶向需要谨慎，因为这种蛋白质发挥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诱导协同有害作用。因此，仅针对α-突触核蛋白可能是不够的。未来应考虑联合治疗。Calabresi等人综述了α-突触核蛋白的生理和病理作用，重点是其突触前和突触后效应。他们讨论了帕金森病临床前模型的发现，探讨了细胞水平的改变如何有助于网络水平病理学的传播。
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. Calabresi et al. review the physiological and pathological roles of alpha-synuclein, focusing on its pre- and post-synaptic effects. Discussing findings from preclinical models of Parkinson’s disease, they explore how alterations at the cellular level contribute to the spread of pathology at the network level.
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影响因子：
15.9
作者：
Bose, Anindita;Petsko, Gregory A.;Studer, Lorenz
通讯作者：
Studer, Lorenz
帕金森氏病焦虑的神经影像学：系统评价。
DOI：
10.1002/mds.28404
发表时间：
2021-03
期刊：
Movement disorders : official journal of the Movement Disorder Society
影响因子：
--
作者：
Carey G;Görmezoğlu M;de Jong JJA;Hofman PAM;Backes WH;Dujardin K;Leentjens AFG
通讯作者：
Leentjens AFG
影响因子：
3.4
作者：
Ghiglieri V;Calabrese V;Calabresi P
通讯作者：
Calabresi P
影响因子：
12.7
作者：
Fanning S;Selkoe D;Dettmer U
通讯作者：
Dettmer U
DOI：
10.3233/jpd-179005
发表时间：
2017
期刊：
Journal of Parkinson's disease
影响因子：
--
作者：
Goedert M;Jakes R;Spillantini MG
通讯作者：
Spillantini MG