The neuroendocrine protein 7B2 suppresses the aggregation of neurodegenerative disease-related proteins.
The neuroendocrine protein 7B2 suppresses the aggregation of neurodegenerative disease-related proteins.
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DOI：
10.1074/jbc.m112.417071
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发表时间：
2013-01-11
期刊：
影响因子：
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通讯作者：
Lindberg I
中科院分区：
文献类型：
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作者：
Helwig M;Hoshino A;Berridge C;Lee SN;Lorenzen N;Otzen DE;Eriksen JL;Lindberg I
背景：神经内分泌蛋白7 B2阻断某些分泌蛋白的聚集。结果如下：7 B2与帕金森和阿尔茨海默病脑中的蛋白质聚集体共定位;阻断Aβ1-40、Aβ1-42和α-突触核蛋白的纤维化;并阻断Aβ1-42诱导的Neuro-2A细胞死亡。结论：7 B2通过调节寡聚体的形成抑制Aβ1-42的细胞毒性。意义：7 B2是一种与神经退行性疾病相关的新型抗聚集分泌伴侣。神经退行性疾病如阿尔茨海默病（AD）和帕金森病（PD）的特征在于错误折叠的富含β-片层的蛋白质的异常聚集，包括AD中的淀粉样蛋白-β（Aβ）衍生肽和tau蛋白以及PD中的α-突触核蛋白。这些蛋白质的正确折叠和组装是由普遍表达的分子伴侣控制的;然而，我们对神经元特异性分子伴侣及其参与神经退行性疾病发病机制的理解是有限的。在这里，我们描述了新的分泌蛋白7 B2，这是广泛表达的神经元和内分泌组织的分子伴侣样功能。在体外实验中，7 B2以1：10的摩尔比有效防止原纤化和Aβ1-42、Aβ1-40和α-突触核蛋白聚集体的形成。在细胞培养实验中，在Neuro-2A细胞培养基中或通过腺病毒7 B2过表达在细胞内加入重组7 B2，可阻断Aβ1-42的神经细胞毒性作用，并显著增加细胞活力。相反，通过RNAi敲低7 B2增加了Aβ1-42诱导的细胞毒性。在AD淀粉样变性模型APP/PSEN 1小鼠的脑中，免疫反应性7 B2与易聚集蛋白及其各自的聚集体共定位。此外，在人类AD和PD受影响大脑的海马和黑质中，7 B2与Aβ斑块和α-突触核蛋白沉积高度共定位，强烈表明生理相关性。我们的数据提供了对7 B2的新功能的深入了解，并将这种神经蛋白确定为与神经退行性疾病相关的抗聚集分子伴侣。
Background: The neuroendocrine protein 7B2 blocks the aggregation of certain secreted proteins. Results: 7B2 co-localizes with protein aggregates in Parkinson and Alzheimer disease brains; blocks the fibrillation of Aβ1–40, Aβ1–42, and α-synuclein; and blocks Aβ1–42-induced Neuro-2A cell death. Conclusion: 7B2 inhibits the cytotoxicity of Aβ1–42 by modulation of oligomer formation. Significance: 7B2 is a novel anti-aggregation secretory chaperone associated with neurodegenerative disease. Neurodegenerative diseases such as Alzheimer (AD) and Parkinson (PD) are characterized by abnormal aggregation of misfolded β-sheet-rich proteins, including amyloid-β (Aβ)-derived peptides and tau in AD and α-synuclein in PD. Correct folding and assembly of these proteins are controlled by ubiquitously expressed molecular chaperones; however, our understanding of neuron-specific chaperones and their involvement in the pathogenesis of neurodegenerative diseases is limited. We here describe novel chaperone-like functions for the secretory protein 7B2, which is widely expressed in neuronal and endocrine tissues. In in vitro experiments, 7B2 efficiently prevented fibrillation and formation of Aβ1–42, Aβ1–40, and α-synuclein aggregates at a molar ratio of 1:10. In cell culture experiments, inclusion of recombinant 7B2, either in the medium of Neuro-2A cells or intracellularly via adenoviral 7B2 overexpression, blocked the neurocytotoxic effect of Aβ1–42 and significantly increased cell viability. Conversely, knockdown of 7B2 by RNAi increased Aβ1–42-induced cytotoxicity. In the brains of APP/PSEN1 mice, a model of AD amyloidosis, immunoreactive 7B2 co-localized with aggregation-prone proteins and their respective aggregates. Furthermore, in the hippocampus and substantia nigra of human AD- and PD-affected brains, 7B2 was highly co-localized with Aβ plaques and α-synuclein deposits, strongly suggesting physiological association. Our data provide insight into novel functions of 7B2 and establish this neural protein as an anti-aggregation chaperone associated with neurodegenerative disease.