Parkin Deficiency Delays Motor Decline and Disease Manifestation in a Mouse Model of Synucleinopathy

In synucleinopathies, including Parkinson's disease, partially ubiquitylated α-synuclein species phosphorylated on serine 129 (PS129-α-synuclein) accumulate abnormally. Parkin, an ubiquitin-protein ligase that is dysfunctional in autosomal recessive parkinsonism, protects against α-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 α-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 PS129-α-synuclein but not PS87-α-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 PS129-α-synuclein-positive neurons. As in Lewy bodies, ubiquitin-immunoreactivity, albeit less abundant, was invariably co-localized with PS129-α-synuclein. During late disease stages, the disease-specific neuropathological features revealed by ubiquitin- and PS129-α-synuclein-specific antibodies were similar in mice with or without Parkin. However, the proportion of PS129-α-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 α-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.

在突触核蛋白病（synucleinopathies）——包括帕金森病——中，丝氨酸129位点磷酸化的部分泛素化α-突触核蛋白（α-synuclein）亚型（PS129-α-synuclein）会出现异常聚集。帕金蛋白（Parkin）是一类在常染色体隐性遗传性帕金森病中功能失活的泛素连接酶（ubiquitin-protein ligase），在多种模型中均可拮抗α-突触核蛋白介导的毒性作用。

本研究通过突触核蛋白病小鼠模型，分析帕金蛋白缺失的生物学效应，旨在探究帕金蛋白与α-突触核蛋白是否共享同一生化通路的可能性。无论是否表达帕金蛋白，此类小鼠均会出现年龄依赖性神经退行性疾病，且发病前会逐渐出现感知运动功能障碍相关行为学测试成绩的进行性下降。该症状伴随PS129-α-synuclein在全脑干及脊髓的神经元胞体与神经突起中沉积，而丝氨酸87位点磷酸化α-突触核蛋白（PS87-α-synuclein）并无此类病理沉积；同时在5%的PS129-α-synuclein阳性神经元中可检测到半胱氨酸天冬氨酸特异性蛋白酶9（caspase 9）的激活。与路易小体（Lewy bodies）的病理特征一致，尽管泛素免疫反应信号强度较弱，但始终与PS129-α-synuclein发生共定位。在疾病晚期阶段，泛素与PS129-α-synuclein特异性抗体所标记的疾病特异性神经病理学特征，在帕金蛋白存在与否的小鼠中无显著差异。然而，在帕金蛋白缺失的小鼠中，被泛素共标记的PS129-α-synuclein免疫阳性神经元胞体与神经突起的占比更低，提示突触核蛋白病的进展程度更轻。此外，在帕金蛋白缺失的小鼠中，由人源α-突触核蛋白过表达引发的感知运动功能障碍与神经退行性表型的出现均显著延迟。

上述研究结果提示，在帕金蛋白相关帕金森病中，存在有效的代偿机制可调控疾病的表型表达。