Changes in proteome solubility indicate widespread proteostatic disruption in mouse models of neurodegenerative disease.
Changes in proteome solubility indicate widespread proteostatic disruption in mouse models of neurodegenerative disease.
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DOI：
10.1007/s00401-018-1895-y
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发表时间：
2018-12
影响因子：
12.7
通讯作者：
Borchelt DR
中科院分区：
文献类型：
--
作者：
Pace MC;Xu G;Fromholt S;Howard J;Crosby K;Giasson BI;Lewis J;Borchelt DR
在神经退行性疾病（如阿尔茨海默病、帕金森病、额颞叶痴呆和肌萎缩侧索硬化症）中，病理性错误折叠蛋白的沉积被认为会加重蛋白质稳态机制的负担，可能导致维持蛋白质组的能力不足。我们实验室之前的工作支持了这一假设，在阿尔茨海默氏淀粉样变性小鼠模型中，淀粉样斑块对胞质蛋白溶解度的影响证明了这一点。在目前的研究中，我们证明蛋白质组溶解度的变化是神经退行性疾病小鼠模型的共同病理。转基因小鼠CNS组织中错误折叠的tau、α-突触核蛋白和突变的超氧化物歧化酶1的病理积累与每种模型中数百种CNS蛋白的溶解度变化有关。我们观察到蛋白质组溶解度的变化是渐进的，并且使用rTg4510诱导tau病理模型，证明这些变化依赖于主要病理蛋白的持续表达。在所有检测的模型中，蛋白质组溶解度的变化是稳健的，易于检测，并提供了一个敏感的指标，蛋白酶抑制破坏。有趣的是，在这些不同的模型中，显示向不溶性转变的蛋白质子集是共同的，这表明蛋白质组的特定子集容易受到蛋白质抑制破坏。总的来说，我们的数据表明，小鼠神经退行性蛋白质病变模型对蛋白质抑制网络施加了负担，从而降低了神经细胞防止异常构象变化的能力，从而改变了数百种丰富的细胞蛋白质的溶解度。
The deposition of pathologic misfolded proteins in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia and amyotrophic lateral sclerosis is hypothesized to burden protein homeostatic (proteostatic) machinery, potentially leading to insufficient capacity to maintain the proteome. This hypothesis has been supported by previous work in our laboratory, as evidenced by the perturbation of cytosolic protein solubility in response to amyloid plaques in a mouse model of Alzheimer’s amyloidosis. In the current study, we demonstrate changes in proteome solubility are a common pathology to mouse models of neurodegenerative disease. Pathological accumulations of misfolded tau, α-synuclein and mutant superoxide dismutase 1 in CNS tissues of transgenic mice was associated with changes in the solubility of hundreds of CNS proteins in each model. We observed that changes in proteome solubility were progressive and, using the rTg4510 model of inducible tau pathology, demonstrated that these changes were dependent upon sustained expression of the primary pathologic protein. In all of the models examined, changes in proteome solubility were robust, easily detected, and provided a sensitive indicator of proteostatic disruption. Interestingly, a subset of the proteins that display a shift towards insolubility were common between these different models, suggesting that a specific subset of the proteome is vulnerable to proteostatic disruption. Overall, our data suggest that neurodegenerative proteinopathies modeled in mice impose a burden on the proteostatic network that diminishes the ability of neural cells to prevent aberrant conformational changes that alter the solubility of hundreds of abundant cellular proteins.
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影响因子：
3.7
作者：
Basso M;Samengo G;Nardo G;Massignan T;D'Alessandro G;Tartari S;Cantoni L;Marino M;Cheroni C;De Biasi S;Giordana MT;Strong MJ;Estevez AG;Salmona M;Bendotti C;Bonetto V
通讯作者：
Bonetto V
DOI：
10.1016/j.bbadis.2014.05.029
发表时间：
2014-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Flach K;Ramminger E;Hilbrich I;Arsalan-Werner A;Albrecht F;Herrmann L;Goedert M;Arendt T;Holzer M
通讯作者：
Holzer M
影响因子：
4.7
作者：
Babu, JR;Geetha, T;Wooten, MW
通讯作者：
Wooten, MW
影响因子：
7.2
作者：
Bosco, Daryl A.;LaVoie, Matthew J.;Ringe, Dagmar
通讯作者：
Ringe, Dagmar
影响因子：
13.8
作者：
Dobson, CM
通讯作者：
Dobson, CM