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热休克蛋白 70 分子伴侣在α-突触核蛋白病的小鼠模型中没有益处。

The HSP70 molecular chaperone is not beneficial in a mouse model of alpha-synucleinopathy.

机构信息

Neuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.

出版信息

PLoS One. 2010 Apr 2;5(4):e10014. doi: 10.1371/journal.pone.0010014.

DOI:10.1371/journal.pone.0010014
PMID:20368804
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2848858/
Abstract

BACKGROUND

Aggregation and misfolded alpha-synuclein is thought to be central in the pathogenesis of Parkinson's disease (PD). Heat-shock proteins (HSPs) that are involved in refolding and degradation processes could lower the aggregate load of alpha-synuclein and thus be beneficial in alpha-synucleinopathies.

METHODOLOGY/PRINCIPAL FINDINGS: We co-overexpressed human A53T point-mutated alpha-synuclein and human HSP70 in mice, both under the control of Thy1 regulatory sequences. Behavior read-outs showed no beneficial effect of HSP70 expression in mice. In contrast, motor coordination, grip strength and weight were even worse in the alpha-synucleinopathy model in the presence of HSP70 overexpression. Biochemical analyses revealed no differences in alpha-synuclein oligomers/aggregates, truncations and phosphorylation levels and alpha-synuclein localization was unchanged in immunostainings.

CONCLUSION/SIGNIFICANCE: Overexpressing HSP70 in a mouse model of alpha-synucleinopathy did not lower the toxic load of alpha-synuclein species and had no beneficial effect on alpha-synuclein-related motor deficits.

摘要

背景

聚合和错误折叠的α-突触核蛋白被认为是帕金森病（PD）发病机制的核心。参与重折叠和降解过程的热休克蛋白（HSPs）可以降低α-突触核蛋白的聚集负荷，因此对α-突触核蛋白病有益。

方法/主要发现：我们在小鼠中共同过表达了受 Thy1 调节序列控制的人 A53T 点突变α-突触核蛋白和人 HSP70。行为检测结果显示 HSP70 表达对小鼠没有有益影响。相比之下，在 HSP70 过表达的情况下，α-突触核蛋白病模型中的运动协调、握力和体重甚至更差。生化分析显示α-突触核蛋白寡聚物/聚集体、截断和磷酸化水平没有差异，免疫染色中α-突触核蛋白的定位也没有改变。

结论/意义：在α-突触核蛋白病的小鼠模型中过表达 HSP70 并没有降低α-突触核蛋白物种的毒性负荷，也没有对α-突触核蛋白相关的运动缺陷产生有益影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/1549dc6e4ac2/pone.0010014.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/30cabaeba255/pone.0010014.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/23017480cd20/pone.0010014.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/d76beffc32dd/pone.0010014.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/5088167f48fa/pone.0010014.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/1549dc6e4ac2/pone.0010014.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/30cabaeba255/pone.0010014.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/23017480cd20/pone.0010014.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/d76beffc32dd/pone.0010014.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/5088167f48fa/pone.0010014.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1384/2848858/1549dc6e4ac2/pone.0010014.g005.jpg

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