Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies
Depletion of 26S proteasomes in mouse brain neurons causes neurodegeneration and Lewy-like inclusions resembling human pale bodies
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DOI：
10.1523/jneurosci.2218-08.2008
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发表时间：
2008-08-13
影响因子：
5.3
通讯作者：
Mayer, R. John
中科院分区：
文献类型：
--
作者：
Bedford, Lynn;Hay, David;Mayer, R. John
泛素阳性的神经元内包涵体是人类主要神经退行性疾病的一致特征，表明泛素蛋白酶体系统的功能障碍是疾病病因学的核心。使用20 S蛋白酶体抑制剂来模拟帕金森病的研究是有争议的。我们首次报道，特别是26 S蛋白酶体功能障碍足以引发神经退行性疾病。在这里，我们描述了新的条件遗传小鼠模型，使用Cre/loxP系统在空间上限制Psmc 1（Rpt 2/S4）的失活，无论是黑质或前脑（例如）的神经元。例如，在一个实施例中，皮质、海马和纹状体）。Psmc 1是26 S蛋白酶体的一个重要亚基，Psmc 1条件性基因敲除小鼠在靶神经元中显示26 S蛋白酶体耗竭，其中20 S蛋白酶体不受影响。特异性泛素介导的蛋白质降解的损害引起神经元内Lewy样包涵体和黑质纹状体通路和前脑区域的广泛神经变性。泛素和α-突触核蛋白神经病理学是明显的，类似于人类路易体，但有趣的是，包涵体含有线粒体。我们通过展示帕金森病患者早期路易体（苍白体）中的线粒体来支持这一观察结果。结果直接证实了神经元中的26 S功能障碍参与神经退行性疾病的病理学。该模型表明，26 S蛋白酶体是必要的正常神经元的稳态和20 S蛋白酶体的活性是不够的神经元的生存。最后，我们提供了第一个可重复的遗传平台，用于识别新的治疗靶点，以减缓或预防神经退行性变。
Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e. g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and alpha-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.