Université Pierre et Marie Curie-Paris 6, CRICM (Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière), UMR-S975, Paris, France.
PLoS One. 2009 Aug 14;4(8):e6629. doi: 10.1371/journal.pone.0006629.
In synucleinopathies, including Parkinson's disease, partially ubiquitylated alpha-synuclein species phosphorylated on serine 129 (P(S129)-alpha-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against alpha-synuclein-mediated toxicity in various models.We analyzed the effects of Parkin deficiency in a mouse model of synucleinopathy to explore the possibility that Parkin and alpha-synuclein act in the same biochemical pathway. Whether or not Parkin was present, these mice developed an age-dependent neurodegenerative disorder preceded by a progressive decline in performance in tasks predictive of sensorimotor dysfunction. The symptoms were accompanied by the deposition of P(S129)-alpha-synuclein but not P(S87)-alpha-synuclein in neuronal cell bodies and neuritic processes throughout the brainstem and the spinal cord; activation of caspase 9 was observed in 5% of the P(S129)-alpha-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with P(S129)-alpha-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and P(S129)-alpha-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of P(S129)-alpha-synuclein-immunoreactive neuronal cell bodies and neurites co-stained for ubiquitin was lower in the absence than in the presence of Parkin, suggesting less advanced synucleinopathy. Moreover, sensorimotor impairment and manifestation of the neurodegenerative phenotype due to overproduction of human alpha-synuclein were significantly delayed in Parkin-deficient mice.These findings raise the possibility that effective compensatory mechanisms modulate the phenotypic expression of disease in parkin-related parkinsonism.
在包括帕金森病在内的突触核蛋白病中，部分泛素化的α-突触核蛋白在丝氨酸 129 上发生磷酸化（P(S129)-α-突触核蛋白）异常积累。Parkin 是一种泛素连接酶，在常染色体隐性遗传帕金森病中失活，可在各种模型中保护α-突触核蛋白介导的毒性。我们分析了突触核蛋白病小鼠模型中 Parkin 缺失的影响，以探讨 Parkin 和α-突触核蛋白是否在相同的生化途径中发挥作用。无论 Parkin 是否存在，这些小鼠都会出现一种年龄依赖性的神经退行性疾病，在此之前，它们在预测感觉运动功能障碍的任务中的表现会逐渐下降。这些症状伴随着 P(S129)-α-突触核蛋白的沉积，但不伴随着 P(S87)-α-突触核蛋白的沉积，沉积发生在脑干和脊髓的神经元胞体和神经突中；在 5%的 P(S129)-α-突触核蛋白阳性神经元中观察到 caspase 9 的激活。与 Lewy 体一样，尽管丰度较低，但泛素免疫反应性总是与 P(S129)-α-突触核蛋白共定位。在疾病晚期，具有或不具有 Parkin 的小鼠中，通过泛素和 P(S129)-α-突触核蛋白特异性抗体揭示的疾病特异性神经病理学特征相似。然而，在缺乏 Parkin 的情况下，P(S129)-α-突触核蛋白免疫反应性神经元胞体和神经突的比例低于存在 Parkin 的情况，表明突触核蛋白病进展程度较低。此外，由于人α-突触核蛋白过表达导致的运动感觉障碍和神经退行性表型的表现，在 Parkin 缺失的小鼠中显著延迟。这些发现提出了一种可能性，即有效的补偿机制调节了与 Parkin 相关的帕金森病中疾病表型的表达。
