Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism.
Aggregated Alpha-Synuclein Inclusions within the Nucleus Predict Impending Neuronal Cell Death in a Mouse Model of Parkinsonism.
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细胞核内聚集的α-突触核蛋白内含物预测帕金森病小鼠模型中即将发生的神经元细胞死亡。
DOI：
10.3390/ijms232315294
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发表时间：
2022-12-04
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
α-突触核蛋白（aSyn）是由SNCA基因编码的14 kD蛋白，在脊椎动物中表达，通常定位于突触前末梢和细胞核。aSyn形成病理性细胞内聚集体，其代表一组称为突触核蛋白病的重要神经变性疾病。先前在人类组织和模型系统中的工作表明，这些聚集体中的一些可以是核内的，但是细胞核内aSyn聚集的意义尚不清楚。我们使用了产生聚集的aSyn核包涵体的小鼠模型。在GFP标记的aSyn转基因小鼠中使用aSyn预形成的原纤维注射，我们能够诱导核aSyn包涵体的形成，并使用多光子显微镜在固定的组织和体内研究它们的性质。此外，我们分析了人类突触核蛋白病患者的组织，以更好地了解这种病理。我们的数据表明，核aSyn包涵体可以通过神经元之间的aSyn传递形成，并且这些核内聚集体具有细胞质Lewy病理学的标志。神经元核aSyn包涵体可以形成不含肌动蛋白的杆状结构，将它们排除在先前描述的核肌动蛋白棒之外。纵向，在体内多光子成像表明，神经元核aSyn包涵体的某些形态预测细胞死亡在14天内。人类多系统萎缩病例含有具有类似核内含物的神经元和神经胶质，但我们无法在路易体痴呆病例中检测到此类内含物。这项研究表明，与核包涵体形成相关的核aSyn功能失调可能在与突触核蛋白病相关的神经变性形式中发挥作用。
Alpha-synuclein (aSyn) is a 14 kD protein encoded by the SNCA gene that is expressed in vertebrates and normally localizes to presynaptic terminals and the nucleus. aSyn forms pathological intracellular aggregates that typify a group of important neurodegenerative diseases called synucleinopathies. Previous work in human tissue and model systems indicates that some of these aggregates can be intranuclear, but the significance of aSyn aggregation within the nucleus is not clear. We used a mouse model that develops aggregated aSyn nuclear inclusions. Using aSyn preformed fibril injections in GFP-tagged aSyn transgenic mice, we were able to induce the formation of nuclear aSyn inclusions and study their properties in fixed tissue and in vivo using multiphoton microscopy. In addition, we analyzed human synucleinopathy patient tissue to better understand this pathology. Our data demonstrate that nuclear aSyn inclusions may form through the transmission of aSyn between neurons, and these intranuclear aggregates bear the hallmarks of cytoplasmic Lewy pathology. Neuronal nuclear aSyn inclusions can form rod-like structures that do not contain actin, excluding them from being previously described nuclear actin rods. Longitudinal, in vivo multiphoton imaging indicates that certain morphologies of neuronal nuclear aSyn inclusions predict cell death within 14 days. Human multiple system atrophy cases contain neurons and glia with similar nuclear inclusions, but we were unable to detect such inclusions in Lewy body dementia cases. This study suggests that the dysregulation of a nuclear aSyn function associated with nuclear inclusion formation could play a role in the forms of neurodegeneration associated with synucleinopathy.
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影响因子：
12.7
作者：
Jiang P;Gan M;Yen SH;Moussaud S;McLean PJ;Dickson DW
通讯作者：
Dickson DW
影响因子：
7.1
作者：
通讯作者：
--
影响因子：
3.3
作者：
Huang, Z.;Xu, Z.;Wu, Y.;Zhou, Y.
通讯作者：
Zhou, Y.
影响因子：
4.8
作者：
Derossi, D;Calvet, S;Prochiantz, A
通讯作者：
Prochiantz, A
影响因子：
2.5
作者：
Lin, WL;DeLucia, MW;Dickson, DW
通讯作者：
Dickson, DW