Er Safak, Airavaara Mikko
Faculty of Pharmacy, Drug Research Program, University of Helsinki, Helsinki, Finland.
Neuroscience Center, University of Helsinki, Helsinki, Finland.
Biochem Soc Trans. 2023 Feb 27;51(1):245-257. doi: 10.1042/BST20220770.
Synucleinopathies constitute a disease family named after alpha-synuclein protein, which is a significant component of the intracellular inclusions called Lewy bodies. Accompanying the progressive neurodegeneration, Lewy bodies and neurites are the main histopathologies of synucleinopathies. The complicated role of alpha-synuclein in the disease pathology makes it an attractive therapeutic target for disease-modifying treatments. GDNF is one of the most potent neurotrophic factors for dopamine neurons, whereas CDNF is protective and neurorestorative with entirely different mechanisms of action. Both have been in the clinical trials for the most common synucleinopathy, Parkinson's disease. With the AAV-GDNF clinical trials ongoing and the CDNF trial being finalized, their effects on abnormal alpha-synuclein accumulation are of great interest. Previous animal studies with an alpha-synuclein overexpression model have shown that GDNF was ineffective against alpha-synuclein accumulation. However, a recent study with cell culture and animal models of alpha-synuclein fibril inoculation has demonstrated the opposite by revealing that the GDNF/RET signaling cascade is required for the protective effect of GDNF on alpha-synuclein aggregation. CDNF, an ER resident protein, was shown to bind alpha-synuclein directly. CDNF reduced the uptake of alpha-synuclein fibrils by the neurons and alleviated the behavioral deficits induced by fibrils injected into the mouse brain. Thus, GDNF and CDNF can modulate different symptoms and pathologies of Parkinson's disease, and perhaps, similarly for other synucleinopathies. Their unique mechanisms for preventing alpha-synuclein-related pathology should be studied more carefully to develop disease-modifying therapies.
突触核蛋白病是一类以α-突触核蛋白命名的疾病家族，α-突触核蛋白是细胞内包涵体路易小体的重要组成部分。随着神经退行性变的进展，路易小体和神经突是突触核蛋白病的主要组织病理学特征。α-突触核蛋白在疾病病理过程中的复杂作用使其成为疾病修饰治疗的一个有吸引力的治疗靶点。胶质细胞源性神经营养因子（GDNF）是对多巴胺能神经元最有效的神经营养因子之一，而睫状神经营养因子（CDNF）具有保护和神经修复作用，其作用机制完全不同。两者都已进入最常见的突触核蛋白病——帕金森病的临床试验。随着腺相关病毒-GDNF临床试验的进行和CDNF试验的完成，它们对异常α-突触核蛋白积累的影响备受关注。先前使用α-突触核蛋白过表达模型的动物研究表明，GDNF对α-突触核蛋白积累无效。然而，最近一项关于α-突触核蛋白原纤维接种的细胞培养和动物模型的研究却得出了相反的结果，该研究表明GDNF/RET信号级联反应是GDNF对α-突触核蛋白聚集产生保护作用所必需的。CDNF是一种内质网驻留蛋白，已被证明可直接与α-突触核蛋白结合。CDNF减少了神经元对α-突触核蛋白原纤维的摄取，并减轻了注射到小鼠脑内的原纤维诱导的行为缺陷。因此，GDNF和CDNF可以调节帕金森病的不同症状和病理，或许对其他突触核蛋白病也同样如此。应更仔细地研究它们预防α-突触核蛋白相关病理的独特机制，以开发疾病修饰疗法。
