Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice
Human α-synuclein-harboring familial Parkinson's disease-linked Ala-53→Thr mutation causes neurodegenerative disease with α-synuclein aggregation in transgenic mice
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DOI：
10.1073/pnas.132197599
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发表时间：
2002-06-25
影响因子：
11.1
通讯作者：
Price, DL
中科院分区：
文献类型：
--
作者：
Lee, MK;Stirling, W;Price, DL
α-突触核蛋白 (alpha-Syn) 突变会导致少数患有家族性 PD 的家系出现帕金森病 (PD)。此外，α-Syn 积累作为路易体和路易神经突的主要成分，神经元内包涵体是 PD 的神经病理学标志。为了更好地了解 α-Syn 生物学变化与 PD 相关神经变性之间的致病关系，我们培育了多个转基因小鼠品系，它们表达高水平的野生型或家族性 PD 相关 Ala-30 --> Pro (A30P) 或 Ala-53 --> Thr (A53T) 人类 α-Syns。表达 A53T 人类 α-Syn（但不表达野生型或 A30P 变体）的小鼠会患上成人发病的神经退行性疾病，并伴有进行性运动功能障碍，最终导致死亡。在病理学上，受影响的小鼠表现出神经元异常（在核周和神经突中），包括 α-Syn 和泛素的病理性积累。与 α-Syn 的异常神经元积累一致，具有病理学的大脑区域表现出去污剂不溶性 α-Syn 和 α-Syn 聚集体的增加。我们的结果表明，与其他 α-Syn 变体相比，A53T 突变体 α-Syn 引起显着更大的体内神经毒性。此外，α-Syn依赖性神经变性与去污剂不溶性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.