Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy.
Loss of tau expression attenuates neurodegeneration associated with α-synucleinopathy.
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tau蛋白表达缺失可减弱与α-突触核蛋白病相关的神经变性
DOI：
10.1186/s40035-022-00309-x
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发表时间：
2022-07-01
影响因子：
12.6
通讯作者：
Lee, Michael K.
中科院分区：
文献类型：
--
作者：
Vermilyea, Scott C.;Christensen, Anne;Meints, Joyce;Singh, Balvindar;Martell-Martinez, Hector;Karim, Md. Razaul;Lee, Michael K.
与α-突触核蛋白（αS）病理学相关的神经元功能障碍和变性被认为是帕金森病和相关路易体痴呆进行性的原因。研究表明αS病理学和tau异常之间存在双向病理关系。我们最近发现，A53 T突变的人αS（HuαS）可导致突触后和认知缺陷，这需要微管相关蛋白tau表达。然而，tau蛋白在αS病理和随后的神经元功能障碍的发展中的作用一直存在争议。在此，我们使用缺乏小鼠tau蛋白表达的α-突触核蛋白病转基因小鼠模型来确定tau蛋白在αS病理学（α-突触核蛋白病）的发作和进展中的作用。将表达A53 T突变体HuαS（TgA 53 T）的转基因小鼠与mTau−/−小鼠杂交，以产生TgA 53 T/mTau−/−。为了在小鼠中更均匀地诱导α-突触核蛋白病，我们在非转基因（nTg）、TgA 53 T、TgA 53 T/mTau−/−和mTau−/−小鼠中肌内注射αS预制原纤维（PFF）。在PFF接种后（dpi）70天分析运动行为，并在40 dpi、70 dpi和末期收集用于生化和神经病理学分析的组织。tau蛋白表达的缺失显著延迟了TgA 53 T模型中运动缺陷的发生和α-突触核蛋白病疾病的进展，这可以通过神经变性和疾病的组织病理学和行为标志物的显著减少以及生存期的显著改善来证明。在体外将PFF应用于原代小鼠海马神经元，证明PFF摄取和加工或pS129 αS聚集作为tau表达的函数没有变化。然而，PFF诱导的神经毒性，包括nTg神经元中的形态缺陷，通过去除tau蛋白来防止。总的来说，我们的数据表明tau可能在αS病理学下游起作用，影响神经元的稳态和存活。这项工作进一步支持了α-突触核蛋白病中tau的研究，以确定新的疾病修饰治疗策略。在线版本包含补充材料，可通过10.1186/s40035-022-00309-x获得。
Neuronal dysfunction and degeneration linked to α-synuclein (αS) pathology is thought to be responsible for the progressive nature of Parkinson’s disease and related dementia with Lewy bodies. Studies have indicated bidirectional pathological relationships between αS pathology and tau abnormalities. We recently showed that A53T mutant human αS (HuαS) can cause post-synaptic and cognitive deficits that require microtubule-associated protein tau expression. However, the role of tau in the development of αS pathology and subsequent neuronal dysfunction has been controversial. Herein, we set out to determine the role of tau in the onset and progression of αS pathology (α-synucleinopathy) using a transgenic mouse model of α-synucleinopathy lacking mouse tau expression. Transgenic mice expressing A53T mutant HuαS (TgA53T) were crossed with mTau−/− mice to generate TgA53T/mTau−/−. To achieve more uniform induction of α-synucleinopathy in mice, we used intramuscular injections of αS preformed fibrils (PFF) in non-transgenic (nTg), TgA53T, TgA53T/mTau−/−, and mTau−/− mice. Motor behavior was analyzed at 70 days post inoculation (dpi) of PFF and tissues for biochemical and neuropathological analysis were collected at 40 dpi, 70 dpi, and end stage. Loss of tau expression significantly delayed the onset of motor deficits in the TgA53T model and the progression of α-synucleinopathy disease, as evidenced by a significant reduction in histopathological and behavioral markers of neurodegeneration and disease, and a significant improvement in survival. In vitro application of PFF to primary mouse hippocampal neurons demonstrated no changes in PFF uptake and processing or pS129 αS aggregation as a function of tau expression. However, PFF-induced neurotoxicity, including morphological deficits in nTg neurons, was prevented with tau removal. Collectively, our data suggest that tau is likely acting downstream of αS pathology to affect neuronal homeostasis and survival. This work further supports the investigation of tau in α-synucleinopathies to identify novel disease-modifying therapeutic strategies. The online version contains supplementary material available at 10.1186/s40035-022-00309-x.
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DOI：
10.1073/pnas.132197599
发表时间：
2002-06-25
影响因子：
11.1
作者：
Lee, MK;Stirling, W;Price, DL
通讯作者：
Price, DL
影响因子：
5.3
作者：
Teravskis, Peter J.;Covelo, Ana;Liao, Dezhi
通讯作者：
Liao, Dezhi
DOI：
10.1093/jnen/61.5.413
发表时间：
2002-05-01
影响因子：
3.2
作者：
Del Tredici, K;Rüb, U;Braak, H
通讯作者：
Braak, H
影响因子：
3.7
作者：
Morris M;Koyama A;Masliah E;Mucke L
通讯作者：
Mucke L
DOI：
10.1523/jneurosci.5367-11.2012
发表时间：
2012-03-07
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Colla E;Coune P;Liu Y;Pletnikova O;Troncoso JC;Iwatsubo T;Schneider BL;Lee MK
通讯作者：
Lee MK