Lewy bodies contain altered α-synuclein in brains of many familiar Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes
Lewy bodies contain altered α-synuclein in brains of many familiar Alzheimer's disease patients with mutations in presenilin and amyloid precursor protein genes
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DOI：
10.1016/s0002-9440(10)65722-7
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发表时间：
1998-11-01
影响因子：
6
通讯作者：
Trojanowski, JQ
中科院分区：
文献类型：
--
作者：
Lippa, CF;Fujiwara, H;Trojanowski, JQ
α-突触核蛋白基因的错义突变会导致家族性帕金森病 (PD)，而 α-突触核蛋白是散发性 PD、LB 痴呆 (DLB) 和阿尔茨海默病 (AD) 的 LB 变体中路易体 (LB) 的主要成分。为了确定 α-突触核蛋白是否是已知早老素 (n = 65) 或淀粉样前体蛋白 (n = 9) 基因突变的家族性 AD (FAD) 患者 LB 的组成部分，我们使用 α-、β- 和 γ-突触核蛋白抗体进行了研究。在 22% 的 FAD 大脑中检测到 α 突触核蛋白抗体，但未检测到 β 或 γ 突触核蛋白抗体，并且 α 突触核蛋白阳性 LB 在杏仁核中数量最多，其中一些 LB 与 tau 阳性神经原纤维缠结共定位。由于 19 个 FAD 杏仁核样本中有 12 个 (63%) 含有 α-突触核蛋白阳性 LB，因此这些内含物在 FAD 大脑中可能比之前报道的更常见。此外，通过免疫电子显微镜观察，α-突触核蛋白抗体装饰了LB丝，蛋白质印迹显示与对照大脑相比，α-突触核蛋白的溶解度降低。 α-突触核蛋白阳性 LB 的存在与任何特定的 FAD 突变无关。这些研究表明，不溶性 α-突触核蛋白聚集成细丝，在许多 FAD 患者中形成 LB，我们推测这些内含物可能会损害 FAD 大脑中受影响神经元的功能和/或活力。
Missense mutations in the alpha-synuclein gene cause familial Parkinson's disease (PD), and alpha-synuclein is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease (AD). To determine whether alpha-synuclein is a component of LBs in familial AD (FAD) patients with known mutations in presenilin (n = 65) or amyloid precursor protein (n = 9) genes, studies were conducted with antibodies to alpha-, beta-, and gamma-synuclein. LBs were detected with alpha- but not beta- or gamma-synuclein antibodies in 22% of FAD brains, and alpha-synuclein-positive LBs were most numerous in amygdala where some LBs co-localized with tau-positive neurofibrillary tangles. As 12 (63%) of 19 FAD amygdala samples contained alpha-synuclein-positive LBs, these inclusions may be more common in FAD brains than previously reported. Furthermore, alpha-synuclein antibodies decorated LB filaments by immunoelectron microscopy, and Western blots revealed that the solubility of alpha-synuclein was reduced compared with control brains. The presence of alpha-synuclein-positive LBs was not associated with any specific FAD mutation. These studies suggest that insoluble alpha-synuclein aggregates into filaments that form LBs in many FAD patients, and we speculate that these inclusions may compromise the function and/or viability of affected neurons in the FAD brain.