E46K Human α-Synuclein Transgenic Mice Develop Lewy-like and Tau Pathology Associated with Age-dependent, Detrimental Motor Impairment
E46K Human α-Synuclein Transgenic Mice Develop Lewy-like and Tau Pathology Associated with Age-dependent, Detrimental Motor Impairment
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DOI：
10.1074/jbc.m111.247965
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发表时间：
2011-10-07
影响因子：
4.8
通讯作者：
Giasson, Benoit I.
中科院分区：
文献类型：
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作者：
Emmer, Kristel L.;Waxman, Elisa A.;Giasson, Benoit I.
突触核病是一组神经退行性疾病，与形成异常的淀粉样包涵体有关，该包涵体由正常溶解的突触前蛋白α-突触核蛋白(α-SYN)组成。帕金森病是这些疾病中最广为人知的，因为它带有被称为路易小体(Lbs)的α-SYN病理性包涵体。α-syn基因的突变，包括E46K错义突变，足以导致帕金森病和其他联核病，如LBS痴呆症。在此，我们描述了在中枢神经系统神经元中表达E46K人α-SYN的转基因小鼠，这些小鼠出现了有害的年龄依赖性运动损伤。这些动物积聚与年龄相关的胞浆内神经元α-SYN包涵体，这些包涵体与疾病平行，并概括了LBS的生化、组织学和形态特征。令人惊讶的是，E46K人α-SYN转基因小鼠的α-SYN包涵体的形态比之前描述的表达神经元A53T人α-SYN的转基因小鼠(M83系)更接近LBS。E46K人类α-SYN小鼠也产生了大量类似神经原纤维缠结的神经元tau包涵体。随后对E46Kα-SYN在细胞模型中诱导tau包涵体的能力的研究表明，蛋白质聚集的直接和间接机制可能参与了在体内观察到的tau包涵体的形成。对表达A53T人α-SYN的症状前转基因小鼠的重新评估表明，小鼠中α-SYN包涵体的形成必须是同步的；然而，包涵体的形成弥漫在神经轴的受影响区域，因此没有包裹体的聚集。总而言之，这些发现为这些异常蛋白质包涵体的形成机制提供了洞察力，并支持了α-SYN聚集体参与人类疾病发病机制的观点。
Synucleinopathies are a group of neurodegenerative disorders associated with the formation of aberrant amyloid inclusions composed of the normally soluble presynaptic protein alpha-synuclein (alpha-syn). Parkinson disease is the most well known of these disorders because it bears alpha-syn pathological inclusions known as Lewy bodies (LBs). Mutations in the gene for alpha-syn, including the E46K missense mutation, are sufficient to cause Parkinson disease as well as other synucleinopathies like dementia with LBs. Herein, we describe transgenic mice expressing E46K human alpha-syn in CNS neurons that develop detrimental age-dependent motor impairments. These animals accumulate age-dependent intracytoplasmic neuronal alpha-syn inclusions that parallel disease and recapitulate the biochemical, histological, and morphological properties of LBs. Surprisingly, the morphology of alpha-syn inclusions in E46K human alpha-syn transgenic mice more closely resemble LBs than the previously described transgenic mice (line M83) that express neuronal A53T human alpha-syn. E46K human alpha-syn mice also develop abundant neuronal tau inclusions that resemble neurofibrillary tangles. Subsequent studies on the ability of E46K alpha-syn to induce tau inclusions in cellular models suggest that both direct and indirect mechanisms of protein aggregation are probably involved in the formation of the tau inclusions observed here in vivo. Re-evaluation of presymptomatic transgenic mice expressing A53T human alpha-syn reveals that the formation of alpha-syn inclusions in mice must be synchronized; however, inclusion formation is diffuse within affected areas of the neuroaxis such that there was no clustering of inclusions. Collectively, these findings provide insights in the mechanisms of formation of these aberrant proteinaceous inclusions and support the notion that alpha-syn aggregates are involved in the pathogenesis of human diseases.