Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein
Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein
复制标题
DOI：
10.1016/s0896-6273(02)00682-7
复制
发表时间：
2002-05-16
期刊：
影响因子：
16.2
通讯作者：
Lee, VMY
中科院分区：
文献类型：
--
作者：
Giasson, BI;Duda, JE;Lee, VMY
α-突触核蛋白病是神经退行性疾病，其病理范围从选择的核群的死亡到整个神经轴的广泛变性。虽然越来越多的证据表明，α-突触核蛋白病变导致神经退行性变，这仍然存在争议。为了探索这个问题，我们产生了在CNS神经元中表达野生型和A53 T人α-突触核蛋白的转基因小鼠。表达突变体而非野生型α-突触核蛋白的小鼠发生严重且复杂的运动障碍，导致瘫痪和死亡。这些动物的年龄依赖性胞浆内神经元α-突触核蛋白包涵体平行疾病发作，和α-突触核蛋白包涵体概括的人类同行的功能。此外，免疫电镜显示，α-突触核蛋白包涵体含有10-16 nm宽的纤维，类似于人类病理包涵体。这些小鼠证明A53 T α-突触核蛋白导致导致神经变性的毒性丝状α-突触核蛋白神经元包涵体的形成。
alpha-Synucleinopathies are neurodegenerative disorders that range pathologically from the demise of select groups of nuclei to pervasive degeneration throughout the neuraxis. Although mounting evidence suggests that alpha-synuclein lesions lead to neurodegeneration, this remains controversial. To explore this issue, we generated transgenic mice expressing wild-type and A53T human alpha-synuclein in CNS neurons. Mice expressing mutant, but not wild-type, alpha-synuclein developed a severe and complex motor impairment leading to paralysis and death. These animals developed age-dependent intracytoplasmic neuronal alpha-synuclein inclusions paralleling disease onset, and the alpha-synuclein inclusions recapitulated features of human counterparts. Moreover, immunoelectron microscopy revealed that the alpha-synuclein inclusions contained 10-16 nm wide fibrils similar to human pathological inclusions. These mice demonstrate that A53T alpha-synuclein leads to the formation of toxic filamentous alpha-synuclein neuronal inclusions that cause neurodegeneration.