αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction
αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction
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DOI：
10.1073/pnas.1005005107
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发表时间：
2010-11-09
影响因子：
11.1
通讯作者：
Chandra, Sreeganga S.
中科院分区：
文献类型：
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作者：
Greten-Harrison, Becket;Polydoro, Manuela;Chandra, Sreeganga S.
突触核蛋白是脊椎动物特有的丰富神经元蛋白家族。它们包括三个密切相关的成员，α-，β-和γ-突触核蛋白。自从α-突触核蛋白的突变被确定为家族性帕金森病的原因以来，它一直是人们密切关注的焦点。尽管它们与疾病相关，但突触核蛋白的正常生理功能仍然难以捉摸。为了解决这个问题，我们产生并表征了α β γ-突触核蛋白敲除小鼠，这些小鼠缺乏该蛋白质家族的所有成员。突触核蛋白的缺失导致突触结构和传递的改变、年龄依赖性神经元功能障碍以及存活率降低。在体内和体外，突触核蛋白表达的废除减少兴奋性突触的大小相似的30%，揭示突触核蛋白是突触前末端大小的重要决定因素。年轻的无突触核蛋白的小鼠表现出改善的基本传输，而老年小鼠表现出显着的递减。突触核蛋白基因敲除小鼠的迟发表型不是由于突触或神经元的丢失，而是反映了突触蛋白组成和轴突结构的特定变化。我们的研究结果表明，突触核蛋白有助于神经系统的长期运作，其生理功能的改变可能有助于帕金森病的发展。
Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, alpha-, beta-, and gamma-synuclein. alpha-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized alpha beta gamma-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by similar to 30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease.