Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice.
Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice.
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发表时间：
2002
影响因子：
11.1
通讯作者：
Michael K. Lee;Wanda Stirling;Yanqun Xu;Xueying Xu;D. Qui;A. Mandir;T. Dawson;N. Copeland;
中科院分区：
文献类型：
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作者：
Michael K. Lee;Wanda Stirling;Yanqun Xu;Xueying Xu;D. Qui;A. Mandir;T. Dawson;N. Copeland;
α-突触核蛋白（α-Syn）的突变在少数家族性帕金森病（PD）家系中引起PD。此外，α-Syn作为路易体和路易神经突的主要组分积累，路易体和路易神经突是PD的神经病理学标志的神经元内包涵体。为了更好地理解alpha-Syn生物学改变与PD相关神经变性之间的致病关系，我们产生了多个转基因小鼠品系，这些小鼠表达高水平的野生型或家族性PD连锁的Ala-30 -> Pro（A30 P）或Ala-53 -> Thr（A53 T）人alpha-Syn。表达A53 T人α-Syn但不表达野生型或A30 P变体的小鼠发展成成年发病的神经变性疾病，具有导致死亡的进行性运动功能障碍。在病理学上，受影响的小鼠表现出神经元异常（在胞体和神经突中），包括α-Syn和泛素的病理性积聚。与a-Syn的异常神经元积聚一致，具有病理学的脑区域表现出洗涤剂不溶性a-Syn和a-Syn聚集体的增加。我们的结果表明，A53 T突变体α-Syn与其他α-Syn变体相比，在体内引起显著更大的神经毒性。此外，α-Syn依赖性神经退行性变与洗涤剂不溶性α-Syn的异常积累有关。
Mutations in alpha-synuclein (alpha-Syn) cause Parkinson's disease (PD) in a small number of pedigrees with familial PD. Moreover, alpha-Syn accumulates as a major component of Lewy bodies and Lewy neurites, intraneuronal inclusions that are neuropathological hallmarks of PD. To better understand the pathogenic relationship between alterations in the biology of alpha-Syn and PD-associated neurodegeneration, we generated multiple lines of transgenic mice expressing high levels of either wild-type or familial PD-linked Ala-30 --> Pro (A30P) or Ala-53 --> Thr (A53T) human alpha-Syns. The mice expressing the A53T human alpha-Syn, but not wild-type or the A30P variants, develop adult-onset neurodegenerative disease with a progressive motoric dysfunction leading to death. Pathologically, affected mice exhibit neuronal abnormalities (in perikarya and neurites) including pathological accumulations of alpha-Syn and ubiquitin. Consistent with abnormal neuronal accumulation of alpha-Syn, brain regions with pathology exhibit increases in detergent-insoluble alpha-Syn and alpha-Syn aggregates. Our results demonstrate that the A53T mutant alpha-Syn causes significantly greater in vivo neurotoxicity as compared with other alpha-Syn variants. Further, alpha-Syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble alpha-Syn.