The protein α-synuclein (αsyn) forms pathologic aggregates in a number of neurodegenerative diseases including Lewy body dementia (LBD) and Parkinson's disease (PD). It is unclear why diseases such as LBD may develop widespread αsyn pathology, while in Alzheimer's disease with amygdala restricted Lewy bodies (AD/ALB) the αsyn aggregates remain localized. The amygdala contains αsyn aggregates in both LBD and in AD/ALB; to understand why αsyn pathology continues to progress in LBD but not in AD/ALB, tissue from the amygdala and other regions were obtained from 14 cases of LBD, 9 cases of AD/ALB, and 4 controls for immunohistochemical and biochemical characterization. Utilizing a panel of previously characterized αsyn antibodies, numerous unique pathologies differentiating LBD and AD/ALB were revealed; particularly the presence of dense neuropil αsyn aggregates, astrocytic αsyn, and αsyn-containing dystrophic neurites within senile plaques. Within LBD, these unique pathologies were predominantly present within the amygdala. Biochemically, the amygdala in LBD prominently contained specific carboxy-truncated forms of αsyn which are highly prone to aggregate, suggesting that the amygdala may be prone to initiate development of αsyn pathology. Similar to carboxy-truncated αsyn, it was demonstrated herein that the presence of aggregation prone A53T αsyn is sufficient to drive misfolding of wild-type αsyn in human disease. Overall, this study identifies within the amygdala in LBD the presence of unique strain-like variation in αsyn pathology that may be a determinant of disease progression.

中文翻译：

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路易体痴呆杏仁核内独特的 α-突触核蛋白病理学：对疾病发生和进展的影响。


蛋白质 α-突触核蛋白 (αsyn) 在许多神经退行性疾病中形成病理聚集体，包括路易体痴呆 (LBD) 和帕金森病 (PD)。目前还不清楚为什么 LBD 等疾病可能会出现广泛的 αsyn 病理，而在杏仁核限制性路易体 (AD/ALB) 的阿尔茨海默氏病中，αsyn 聚集体仍然局限于局部。杏仁核在 LBD 和 AD/ALB 中都含有 αsyn 聚集体；为了了解为什么 αsyn 病理学在 LBD 中持续进展，但在 AD/ALB 中没有进展，我们从 14 例 LBD 病例、9 例 AD/ALB 病例和 4 例对照中获取了杏仁核和其他区域的组织，用于免疫组织化学和生化表征。利用一组先前表征的 αsyn 抗体，揭示了区分 LBD 和 AD/ALB 的许多独特病理学；特别是老年斑内存在致密的神经纤维 αsyn 聚集体、星形细胞 αsyn 和含有 αsyn 的营养不良性神经突。在 LBD 中，这些独特的病理主要存在于杏仁核内。从生化角度来看，LBD 中的杏仁核显着含有特定的羧基截短形式的 αsyn，这些αsyn 很容易聚集，这表明杏仁核可能容易引发 αsyn 病理学的发展。与羧基截短的αsyn类似，本文证明易于聚集的A53T αsyn的存在足以驱动人类疾病中野生型αsyn的错误折叠。总体而言，这项研究发现 LBD 的杏仁核中存在独特的 αsyn 病理学变异，这可能是疾病进展的决定因素。