Neurodegeneration with brain iron accumulation, type 1 is characterized by α-, β-, and γ-synuclein neuropathology
Neurodegeneration with brain iron accumulation, type 1 is characterized by α-, β-, and γ-synuclein neuropathology
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DOI：
10.1016/s0002-9440(10)64548-8
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发表时间：
2000-08-01
影响因子：
6
通讯作者：
Trojanowski, JQ
中科院分区：
文献类型：
--
作者：
Galvin, JE;Giasson, B;Trojanowski, JQ
神经变性伴脑铁蓄积1型（NBIA 1）或Hallervorden-Spatz综合征是一种罕见的神经变性疾病，其临床特征为帕金森综合征、认知障碍、假延髓特征以及小脑共济失调，神经病理学特征为苍白球、红核和黑质中的神经元丢失、神经胶质增生和铁沉积。NBIA 1的标志性病理损伤是轴突球状体，但也发生路易体（LB）样神经元内包涵体、胶质包涵体和罕见的神经元缠结。在这里，我们表明，有一个积累的α-突触核蛋白（α S）在LB样夹杂物，胶质夹杂物，和球体在三个NBIA 1患者的大脑。此外，β-突触核蛋白（β S）和γ-突触核蛋白（γ S）的免疫反应性检测球状体，但没有在LB样或胶质夹杂物。蛋白质印迹分析表明，NBIA 1脑的高盐溶性和Triton X-100不溶性/十二烷基硫酸钠可溶性部分中存在高分子量α S聚集体。值得注意的是，与对照脑相比，Triton X-100可溶性组分中的α S水平显著降低，并且与其他突触核蛋白病不同，不溶性α S不在甲酸可溶性组分中积累。这些发现通过在NBIA 1的发病机制中涉及α S、β S和γ S扩展了神经退行性突触核蛋白病的概念。
Neurodegeneration with brain iron accumulation, type 1 (NBIA 1), or Hallervorden-Spatz syndrome, is a rare neurodegenerative disorder characterized clinically by Parkinsonism, cognitive impairment, pseudobulbar features, as well as cerebellar ataxia, and neuropathologically by neuronal loss, gliosis, and iron deposition in the globus pallidus, red nucleus, and substantia nigra. The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur. Here we show that there is an accumulation of alpha-synuclein (alpha S) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients. Further, beta-synuclein (beta S) and gamma-synuclein (gamma S) immunoreactivity was detected in spheroids but not in LB-like or glial inclusions. Western blot analysis demonstrated high-molecular weight alpha S aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain. Significantly, the levels of alpha S were markedly reduced in the Triton X-100-soluble fractions compared to control brain, and unlike other synucleinopathies, insoluble alpha S did not accumulate in the formic acid-soluble fraction. These findings expand the concept of neurodegenerative synucleinopathies by Implicating alpha S, beta S, and gamma S in the pathogenesis of NBIA 1.