Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy.
Parkin deficiency delays motor decline and disease manifestation in a mouse model of synucleinopathy.
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DOI：
10.1371/journal.pone.0006629
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发表时间：
2009-08-14
期刊：
影响因子：
3.7
通讯作者：
Corti O
中科院分区：
文献类型：
--
作者：
Fournier M;Vitte J;Garrigue J;Langui D;Dullin JP;Saurini F;Hanoun N;Perez-Diaz F;Cornilleau F;Joubert C;Ardila-Osorio H;Traver S;Duchateau R;Goujet-Zalc C;Paleologou K;Lashuel HA;Haass C;Duyckaerts C;Cohen-Salmon C;Kahle PJ;Hamon M;Brice A;Corti O
在包括帕金森病在内的突触核蛋白病中，丝氨酸129上磷酸化的部分泛素化α-突触核蛋白（PS129-α-突触核蛋白）异常积累。Parkin是一种在常染色体隐性帕金森综合征中功能失调的泛素-蛋白连接酶，在各种模型中保护免受α-突触核蛋白介导的毒性。我们分析了Parkin缺乏对突触核蛋白病小鼠模型的影响，以探讨Parkin和α-突触核蛋白在相同生化途径中起作用的可能性。无论帕金是否存在，这些小鼠都出现了年龄依赖性神经退行性疾病，之前在预测感觉运动功能障碍的任务中表现进行性下降。这些症状伴随着PS129-α-突触核蛋白（而非PS 87-α-突触核蛋白）在整个脑干和脊髓的神经元细胞体和神经炎过程中的沉积;在5%的PS129-α-突触核蛋白阳性神经元中观察到半胱天冬酶9的激活。与路易体一样，泛素免疫反应性虽然不太丰富，但总是与PS129-α-突触核蛋白共定位。在晚期疾病阶段，由泛素和PS129-α-突触核蛋白特异性抗体显示的疾病特异性神经病理学特征在有或没有帕金的小鼠中相似。然而，PS 129-α-突触核蛋白免疫反应性神经元胞体和神经突的泛素共染色比例在不存在Parkin的情况下低于存在Parkin的情况，表明较不先进的突触核蛋白病。此外，由于人α-突触核蛋白的过度产生而导致的感觉运动障碍和神经退行性表型的表现在帕金森病缺陷小鼠中显著延迟。这些发现提出了一种可能性，即有效的代偿机制调节帕金森相关性帕金森综合征疾病的表型表达。
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.
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影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
DOI：
10.1073/pnas.0711053105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Gorbatyuk, Oleg S.;Li, Shoudong;Muzyczka, Nicholas
通讯作者：
Muzyczka, Nicholas
影响因子：
4.2
作者：
Freichel, Christian;Neumann, Manuela;Kahle, Philipp J.
通讯作者：
Kahle, Philipp J.
影响因子：
168.9
作者：
Ibáñez, P;Bonnet, AM;Brice, A
通讯作者：
Brice, A