泛素连接酶Hrd1介导的tau蛋白降解
摘要
神经细胞中的tau蛋白异常聚集是许多神经退行性疾病共有的病理特征,例如在阿尔茨海默病(Alzheimer’s disease, AD),进行性核上瘫(progressive supranuclear palsy)及第17号染色体异常导致的额颞叶型痴呆伴巴金森症(frontotemporal dementia with Parkinsonism linked to chromosome 17, FTDP-17),这些疾病统称为tau蛋白病(tauopathy)。我们的前期研究发现,人类的泛素连接酶Hrd1和tau在AD病人的皮质和海马神经元内有共定位。且Hrd1的表达和异常磷酸化tau的聚集存在负相关。我们在细胞模型上观察到Hrd1的表达可以减少tau的毒性,并发现该作用与Hrd1能降低tau蛋白总体水平有关。在上述研究的基础上,本文进一步探讨了Hrd1减少细胞内tau蛋白水平的相关机制。这不仅有助于进一步认识Hrd1的功能和tau蛋白病的病理机制,也为以Hrd1为靶点的药物设计和筛选提供技术平台。
目的:
观察Hrd1能减少细胞内tau蛋白水平是否与其介导tau降解有关及其降解机制。
方法:
将pEGFP-C1-tau真核细胞表达质粒与野生型Hrd1或酶失活型Hrd1C1A转染293T细胞,然后用Western blot方法检测细胞内相关蛋白的水平;同时用GSK-3β诱导tau过度磷酸化,观察Hrd1过度磷酸化的tau降解的影响。用CHX示踪法观察蛋白质的降解;用免疫荧光双标及免疫沉淀法观察Hrd1和tau的相互作用。
结果:
1.Hrd1降低细胞内磷酸化及非磷酸化tau的水平
采用非神经来源的293T细胞株,转染GFP-tau、wtHrd1和Hrd1C1A质粒,并用GSK-3β共转染细胞以诱导tau蛋白磷酸化。结果显示,转染后16-24 h,共转染Hrd1的细胞荧光减弱。Western blot结果显示:与单独转染tau质粒的细胞相比,共转染Hrd1的细胞内磷酸化及非磷酸化tau的水平都明显减少,而共转染Hrd1C1A则对细胞内tau的水平没有明显影响。提示,Hrd1能降低细胞内磷酸化及非磷酸化tau的总体水平,这可能是Hrd1减少tau毒性的原因。
2.Hrd1促进tau蛋白的降解
为了进一步观察tau蛋白的减少是否由于tau降解增加所致,我们在转染后24 h,在细胞的培养上清液中加入放线菌酮(CHX)以阻断tau的蛋白合成,并于加入CHX后4 h,8 h,16 h分别收取细胞,用免疫印记分析tau的水平。结果显示共转染Hrd1的细胞,tau蛋白的清除加快。表明Hrd1可以促进tau的降解。
3.Hrd1促进磷酸化tau蛋白的降解
年龄相关的NFTs的形成具有神经毒性,高度磷酸化的tau在这个过程中具有重要作用。以前的研究表明泛素连接酶CHIP可以识别磷酸化的tau蛋白,并且在tau蛋白上加上泛素。我们在293T细胞中共转染编码tau和GSK-3β的质粒来诱导tau的磷酸化。结果发现GSK-3β磷酸化后tau蛋白的总体水平提高。这个可能由于tau磷酸化后稳定性提高的缘故。当共转染Hrd1时,Hrd1降低了GSK-3β诱导的磷酸化tau的总量。CHX实验表明wtHrd1可以促进磷酸化tau蛋白的降解。这些结果表明Hrd1可以促进磷酸化tau蛋白的降解。
4.蛋白酶体参与Hrd1介导的tau降解
有报道显示,蛋白酶体可以降解tau蛋白。为了观察蛋白酶体是否参与了Hrd1介导的tau蛋白降解,我们在293T细胞内转染tau或共转染tau和Hrd1,在收取细胞前4 h,培养液内加入蛋白酶体抑制剂MG132或溶酶体抑制剂氯化铵。结果表明,蛋白酶体抑制剂MG132可以稳定tau蛋白的表达,而氯化铵不能稳定tau的表达。当用N-乙基顺丁烯二酰亚胺(NEM)抑制去泛素化后,我们可以观察到高分子量tau的聚集,这些结果表明蛋白酶体参与了Hrd1介导的tau蛋白的降解。
5.Hrd1与tau蛋白的相互作用
我们以前的研究发现,Hrd1可加强胞质蛋白带有扩展型多聚谷氨酰胺Huntingtin的降解。Hrd1是否也可以与胞质蛋白tau相互作用呢?为了回答这个问题,我们首先进行了免疫共沉淀(IP)实验。在293T细胞内共转染tau和Hrd1的质粒,24h后收集细胞并裂解,然后用单克隆抗体tau-5进行免疫沉淀细胞裂解液中的tau蛋白,再用免疫印迹(IB)法检测Hrd1是否可以被tau共沉淀下来。结果发现,在IP tau时,同时把Hrd1共沉淀下来,而且这种作用是不依赖于Hrd1的E3活性的。同时,我们使用免疫荧光双标时发现,Hrd1与tau在细胞内有共定位。提示Hrd1与tau蛋白存在相互作用。
6.Hrd1增强tau的泛素化
为了更进一步确定Hrd1可以泛素化tau蛋白,我们在293T细胞内共转染编码Hrd1,His-tau,ubiquitin蛋白的质粒。蛋白酶体抑制剂MG132用来抑制泛素化tau的降解。我们发现Hrd1的过表达可以增加高分子量的tau,当用GFP-tau质粒转染细胞时,也得到了同样的结果。在免疫沉淀实验中,抑制蛋白酶体活性后,转染Hrd1质粒的细胞tau的泛素化明显增强。这些高分子量tau的形成与tau的泛素化有关。为了了解tau磷酸化对Hrd1介导的tau泛素化的影响,我们在293T细胞内共转染编码GSK-3β的质粒。结果发现,在共转染GSK-3β的细胞内,高分子量tau蛋白的量显著增加,提示GSK-3β诱导的磷酸化可以稳定泛素化的tau蛋白。
结论:
以上研究结果表明,Hrd1可以促进细胞内过度表达的磷酸化和非磷酸化tau的降解,这种作用依赖其E3活性;泛素-蛋白酶体通路参与了Hrd1介导的tau蛋白降解,这可能是Hrd1减轻tau毒性,保护细胞的原因之一。
Aberrant aggregates of tau have been documented a common feature of many neurodegenerative diseases, collectively called tauopathy, including Alzheimer’s disease, progressive supranuclear palsy and frontotemporal dementia with Parkinsonism linked to chromosome 17. Our previous studies found that Hrd1 and tau co-localized in cortex and hippocampal neurons of AD. There is an inverse relationship between Hrd1 and aggregated tau. We found that the expression of Hrd1 can decrease the total level of tau in cell models. On the basic of these studies, we investigated the mechanism of Hrd1 decreased the level of tau. Thus it would be helpful not only to further elucidate the pathological mechanism of tau, but also to offer theoretic basis for drug screening and therapy for patients with tauopathies based on Hrd1 target.
OBJECTIVE:
The purposes of this study were to investigate whether Hrd1 can enhance tau degradation through ubiquitin-proteasome pathway.
METHODS:
The plasmid encoding human tau was constructed and transfected to 293T cells along with wt-Hrd1 or Hrd1C1A (a mutant of Hrd1 with loss of E3 activity) using Lipofactamine 2000. The plasmid encoding GSK-3βwas transfected to cells to induce tau phosphorylation. Fluorescent microscopy and cofocal microscopy were used to observe cell morphology; Western blotting was used to determine the levels of proteins; Immunoprecipatation and immunofluorescent staining were used to observe the interaction and coexpression of tau and Hrd1.
RESULTS:
1. Hrd1 decreases the total level of tau in 293T cells
To test whether Hrd1 can decrease the level of tau, we transfected tau or tau plus Hrd1 to 293T cells. It was found that the fluorescent intensity of GFP-tau in the cells was attenuated when co-transfected with Hrd1, compared with that transfected with tau alone. As the control, Hrd1 did not affect the fluorescent intensity of GFP vector. Meanwhile, Western blotting showed that cellular level of tau was decreased by cotransfected with wild type Hrd1, but not Hrd1C1A, a type Hrd1 with the loss of E3 activity. This indicates that Hrd1 decreased the total level of tau.
2. Hrd1 facilitates tau degradation
To address whether the suppression on the total level of tau is correlated with the degradation of tau, cycloheximide (CHX) chase analysis was used to examine its rate of disappearance after protein synthesis was blocked. We chose CHX chase analysis since it has been widely used in determining ER-anchored E3s-mediated degradation of proteins in both yeast and mammalian cells. Cells were transfected either with tau alone or with tau plus Hrd1. 24 h after transfection, cells were treated with CHX and were chased for 4, 8, and 16 h. Levels of tau were determined by IB. The results showed that Hrd1 promoted tau elimination. These data indicate that Hrd1 removes tau by facilitating its degradation.
3. Hrd1 facilitates phosphorylated tau degradation
Hyperphosphorylation of tau is crucial in the age-related formation of NFTs which is correlated well with neurotoxicity. The previous studies demonstrated that tau phosphorylation is a recognition requirement for the addition of ubiquitin by the ubiquitin ligase CHIP. We wondered whether ubiquitin ligase Hrd1 targets phosphorylated tau for proteasomal degradation. To verify this question, we cotransfected the plasmids encoding tau and GSK-3βto 293T cells to induce tau phosphorylation, based on the report that GSK-3β-induced hyperphosphorylation leads to the formation of paired helical filament (PHF)-like tau. We found that the total level of tau elevated after phosphorylation. This may be due to the increase of tau stability after phosphorylation. Hrd1 reduced the total amount of GSK-3β-induced phosphorylation of tau when it was cotransfected. This suggests that Hrd1 facilitated the degradation of phosphorylated tau.
4. Proteasome is involved in Hrd1-mediated tau degradation
Tau can be degraded by proteasome. Hrd1 should target tau for proteasomal degradation in terms of the requirement of an intact RING finger of Hrd1 in tau degradation. To address this issue, we determined the levels of tau in 293T cells cotransfected with tau plus Hrd1 after treatment with the proteasome inhibitor MG132 and lysosome inhibitor ammonium chloride. The result shows that inhibition of proteasome activity by MG132 stabilized tau in the lysate either expressing Hrd1 or not, while ammonium chloride did not stabilize the levels of tau. When deubiquitination was inhibited by 5mM N-ethylmaleimide (NEM, Sigma), we observed high molecular weight tau accumulation stained with tau-5 antibody, suggesting proteasome involves in Hrd1-mediated tau degradation.
5. Hrd1 interacts with tau and enhances tau ubiquitination
In our previous report, we found the cytosolic protein polyglutamine-containing huntingtin is a substrate for Hrd1. We wondered whether Hrd1 was able to interact with and ubiquitinate tau, although Hrd1 is an ER membrane protein and tau is the cytosolic protein. To test this, we first conducted co-immunoprecipitation experiments. Myc-tagged Hrd1 was cotransfected into 293T cells with tau and then immunoprecipitation was performed with the monoclonal tau-5 antibody. Detection of co-immunoprecipitating Hrd1 was performed by western blotting with monoclonal anti-myc antibody. Hrd1 was found to co-immunoprecipitate with tau, which did not depend on its E3 activity.
To further ascertain whether Hrd1 ubiquitinates tau, 293T cells were cotransfected with myc-tagged Hrd1, His-tagged tau, and myc-tagged ubiquitin. High molecular weight tau was used as a potential indicator of ubiquitination. Proteasome inhibitor MG132 was used to block possibly ubiquitinated tau degradation. We found that Hrd1 overexpression increased high molecular weight forms of tau. We obtained the same result when His-tau was replaced with GFP-tau. Immunoprecipitated tau showed prominent anti-ubiquitin immunoreactivity in Hrd1-expressing cells. This suggests that the formation of high molecular weight forms of tau correlates with the increased ubiquitination. To characterize the effect of phosphorylation on Hrd1-mediated tau ubiquitination, the plasmid encoding GSK-3βwas cotransfected into the cells. the amount of high molecular weight tau increased dramatically in the cells expressing GSK-3β, suggesting that GSK-3β-induced phosphorylation can stabilize ubiquitinated tau, which may have potential functional implications for the role of ubiquitination in tau biology.
CONCLUSIONS:
These results suggest that Hrd1 facilitates tau degradation, which may be at least partially associated with ubiquitin-proteosome pathway.
目的:
观察Hrd1能减少细胞内tau蛋白水平是否与其介导tau降解有关及其降解机制。
方法:
将pEGFP-C1-tau真核细胞表达质粒与野生型Hrd1或酶失活型Hrd1C1A转染293T细胞,然后用Western blot方法检测细胞内相关蛋白的水平;同时用GSK-3β诱导tau过度磷酸化,观察Hrd1过度磷酸化的tau降解的影响。用CHX示踪法观察蛋白质的降解;用免疫荧光双标及免疫沉淀法观察Hrd1和tau的相互作用。
结果:
1.Hrd1降低细胞内磷酸化及非磷酸化tau的水平
采用非神经来源的293T细胞株,转染GFP-tau、wtHrd1和Hrd1C1A质粒,并用GSK-3β共转染细胞以诱导tau蛋白磷酸化。结果显示,转染后16-24 h,共转染Hrd1的细胞荧光减弱。Western blot结果显示:与单独转染tau质粒的细胞相比,共转染Hrd1的细胞内磷酸化及非磷酸化tau的水平都明显减少,而共转染Hrd1C1A则对细胞内tau的水平没有明显影响。提示,Hrd1能降低细胞内磷酸化及非磷酸化tau的总体水平,这可能是Hrd1减少tau毒性的原因。
2.Hrd1促进tau蛋白的降解
为了进一步观察tau蛋白的减少是否由于tau降解增加所致,我们在转染后24 h,在细胞的培养上清液中加入放线菌酮(CHX)以阻断tau的蛋白合成,并于加入CHX后4 h,8 h,16 h分别收取细胞,用免疫印记分析tau的水平。结果显示共转染Hrd1的细胞,tau蛋白的清除加快。表明Hrd1可以促进tau的降解。
3.Hrd1促进磷酸化tau蛋白的降解
年龄相关的NFTs的形成具有神经毒性,高度磷酸化的tau在这个过程中具有重要作用。以前的研究表明泛素连接酶CHIP可以识别磷酸化的tau蛋白,并且在tau蛋白上加上泛素。我们在293T细胞中共转染编码tau和GSK-3β的质粒来诱导tau的磷酸化。结果发现GSK-3β磷酸化后tau蛋白的总体水平提高。这个可能由于tau磷酸化后稳定性提高的缘故。当共转染Hrd1时,Hrd1降低了GSK-3β诱导的磷酸化tau的总量。CHX实验表明wtHrd1可以促进磷酸化tau蛋白的降解。这些结果表明Hrd1可以促进磷酸化tau蛋白的降解。
4.蛋白酶体参与Hrd1介导的tau降解
有报道显示,蛋白酶体可以降解tau蛋白。为了观察蛋白酶体是否参与了Hrd1介导的tau蛋白降解,我们在293T细胞内转染tau或共转染tau和Hrd1,在收取细胞前4 h,培养液内加入蛋白酶体抑制剂MG132或溶酶体抑制剂氯化铵。结果表明,蛋白酶体抑制剂MG132可以稳定tau蛋白的表达,而氯化铵不能稳定tau的表达。当用N-乙基顺丁烯二酰亚胺(NEM)抑制去泛素化后,我们可以观察到高分子量tau的聚集,这些结果表明蛋白酶体参与了Hrd1介导的tau蛋白的降解。
5.Hrd1与tau蛋白的相互作用
我们以前的研究发现,Hrd1可加强胞质蛋白带有扩展型多聚谷氨酰胺Huntingtin的降解。Hrd1是否也可以与胞质蛋白tau相互作用呢?为了回答这个问题,我们首先进行了免疫共沉淀(IP)实验。在293T细胞内共转染tau和Hrd1的质粒,24h后收集细胞并裂解,然后用单克隆抗体tau-5进行免疫沉淀细胞裂解液中的tau蛋白,再用免疫印迹(IB)法检测Hrd1是否可以被tau共沉淀下来。结果发现,在IP tau时,同时把Hrd1共沉淀下来,而且这种作用是不依赖于Hrd1的E3活性的。同时,我们使用免疫荧光双标时发现,Hrd1与tau在细胞内有共定位。提示Hrd1与tau蛋白存在相互作用。
6.Hrd1增强tau的泛素化
为了更进一步确定Hrd1可以泛素化tau蛋白,我们在293T细胞内共转染编码Hrd1,His-tau,ubiquitin蛋白的质粒。蛋白酶体抑制剂MG132用来抑制泛素化tau的降解。我们发现Hrd1的过表达可以增加高分子量的tau,当用GFP-tau质粒转染细胞时,也得到了同样的结果。在免疫沉淀实验中,抑制蛋白酶体活性后,转染Hrd1质粒的细胞tau的泛素化明显增强。这些高分子量tau的形成与tau的泛素化有关。为了了解tau磷酸化对Hrd1介导的tau泛素化的影响,我们在293T细胞内共转染编码GSK-3β的质粒。结果发现,在共转染GSK-3β的细胞内,高分子量tau蛋白的量显著增加,提示GSK-3β诱导的磷酸化可以稳定泛素化的tau蛋白。
结论:
以上研究结果表明,Hrd1可以促进细胞内过度表达的磷酸化和非磷酸化tau的降解,这种作用依赖其E3活性;泛素-蛋白酶体通路参与了Hrd1介导的tau蛋白降解,这可能是Hrd1减轻tau毒性,保护细胞的原因之一。
Aberrant aggregates of tau have been documented a common feature of many neurodegenerative diseases, collectively called tauopathy, including Alzheimer’s disease, progressive supranuclear palsy and frontotemporal dementia with Parkinsonism linked to chromosome 17. Our previous studies found that Hrd1 and tau co-localized in cortex and hippocampal neurons of AD. There is an inverse relationship between Hrd1 and aggregated tau. We found that the expression of Hrd1 can decrease the total level of tau in cell models. On the basic of these studies, we investigated the mechanism of Hrd1 decreased the level of tau. Thus it would be helpful not only to further elucidate the pathological mechanism of tau, but also to offer theoretic basis for drug screening and therapy for patients with tauopathies based on Hrd1 target.
OBJECTIVE:
The purposes of this study were to investigate whether Hrd1 can enhance tau degradation through ubiquitin-proteasome pathway.
METHODS:
The plasmid encoding human tau was constructed and transfected to 293T cells along with wt-Hrd1 or Hrd1C1A (a mutant of Hrd1 with loss of E3 activity) using Lipofactamine 2000. The plasmid encoding GSK-3βwas transfected to cells to induce tau phosphorylation. Fluorescent microscopy and cofocal microscopy were used to observe cell morphology; Western blotting was used to determine the levels of proteins; Immunoprecipatation and immunofluorescent staining were used to observe the interaction and coexpression of tau and Hrd1.
RESULTS:
1. Hrd1 decreases the total level of tau in 293T cells
To test whether Hrd1 can decrease the level of tau, we transfected tau or tau plus Hrd1 to 293T cells. It was found that the fluorescent intensity of GFP-tau in the cells was attenuated when co-transfected with Hrd1, compared with that transfected with tau alone. As the control, Hrd1 did not affect the fluorescent intensity of GFP vector. Meanwhile, Western blotting showed that cellular level of tau was decreased by cotransfected with wild type Hrd1, but not Hrd1C1A, a type Hrd1 with the loss of E3 activity. This indicates that Hrd1 decreased the total level of tau.
2. Hrd1 facilitates tau degradation
To address whether the suppression on the total level of tau is correlated with the degradation of tau, cycloheximide (CHX) chase analysis was used to examine its rate of disappearance after protein synthesis was blocked. We chose CHX chase analysis since it has been widely used in determining ER-anchored E3s-mediated degradation of proteins in both yeast and mammalian cells. Cells were transfected either with tau alone or with tau plus Hrd1. 24 h after transfection, cells were treated with CHX and were chased for 4, 8, and 16 h. Levels of tau were determined by IB. The results showed that Hrd1 promoted tau elimination. These data indicate that Hrd1 removes tau by facilitating its degradation.
3. Hrd1 facilitates phosphorylated tau degradation
Hyperphosphorylation of tau is crucial in the age-related formation of NFTs which is correlated well with neurotoxicity. The previous studies demonstrated that tau phosphorylation is a recognition requirement for the addition of ubiquitin by the ubiquitin ligase CHIP. We wondered whether ubiquitin ligase Hrd1 targets phosphorylated tau for proteasomal degradation. To verify this question, we cotransfected the plasmids encoding tau and GSK-3βto 293T cells to induce tau phosphorylation, based on the report that GSK-3β-induced hyperphosphorylation leads to the formation of paired helical filament (PHF)-like tau. We found that the total level of tau elevated after phosphorylation. This may be due to the increase of tau stability after phosphorylation. Hrd1 reduced the total amount of GSK-3β-induced phosphorylation of tau when it was cotransfected. This suggests that Hrd1 facilitated the degradation of phosphorylated tau.
4. Proteasome is involved in Hrd1-mediated tau degradation
Tau can be degraded by proteasome. Hrd1 should target tau for proteasomal degradation in terms of the requirement of an intact RING finger of Hrd1 in tau degradation. To address this issue, we determined the levels of tau in 293T cells cotransfected with tau plus Hrd1 after treatment with the proteasome inhibitor MG132 and lysosome inhibitor ammonium chloride. The result shows that inhibition of proteasome activity by MG132 stabilized tau in the lysate either expressing Hrd1 or not, while ammonium chloride did not stabilize the levels of tau. When deubiquitination was inhibited by 5mM N-ethylmaleimide (NEM, Sigma), we observed high molecular weight tau accumulation stained with tau-5 antibody, suggesting proteasome involves in Hrd1-mediated tau degradation.
5. Hrd1 interacts with tau and enhances tau ubiquitination
In our previous report, we found the cytosolic protein polyglutamine-containing huntingtin is a substrate for Hrd1. We wondered whether Hrd1 was able to interact with and ubiquitinate tau, although Hrd1 is an ER membrane protein and tau is the cytosolic protein. To test this, we first conducted co-immunoprecipitation experiments. Myc-tagged Hrd1 was cotransfected into 293T cells with tau and then immunoprecipitation was performed with the monoclonal tau-5 antibody. Detection of co-immunoprecipitating Hrd1 was performed by western blotting with monoclonal anti-myc antibody. Hrd1 was found to co-immunoprecipitate with tau, which did not depend on its E3 activity.
To further ascertain whether Hrd1 ubiquitinates tau, 293T cells were cotransfected with myc-tagged Hrd1, His-tagged tau, and myc-tagged ubiquitin. High molecular weight tau was used as a potential indicator of ubiquitination. Proteasome inhibitor MG132 was used to block possibly ubiquitinated tau degradation. We found that Hrd1 overexpression increased high molecular weight forms of tau. We obtained the same result when His-tau was replaced with GFP-tau. Immunoprecipitated tau showed prominent anti-ubiquitin immunoreactivity in Hrd1-expressing cells. This suggests that the formation of high molecular weight forms of tau correlates with the increased ubiquitination. To characterize the effect of phosphorylation on Hrd1-mediated tau ubiquitination, the plasmid encoding GSK-3βwas cotransfected into the cells. the amount of high molecular weight tau increased dramatically in the cells expressing GSK-3β, suggesting that GSK-3β-induced phosphorylation can stabilize ubiquitinated tau, which may have potential functional implications for the role of ubiquitination in tau biology.
CONCLUSIONS:
These results suggest that Hrd1 facilitates tau degradation, which may be at least partially associated with ubiquitin-proteosome pathway.
引文
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6. Lennox G, Lowe J, Morrell K, Landon M, Mayer RJ. Ubiquitin is a component of neurofibrillary tangles in a variety of neurodegenerative diseases. Neurosci Lett, 1988, 94 (1-2) : 211-7.
7. David DC, Layfield R, Serpell L, Narain Y, Goedert M, Spillantini MG. Proteasomal degradation of tau protein. J Neurochem, 2002, 83(1) : 176-85.
8. Richter-Landsberq C , Bauer NG. Tau-inclusion body formation inoligodendroglia: the role of stress proteins and proteasome inhibition. Int J Dev Neurosci, 2004, 22(7) : 443-51.
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12. Hatakeyama S, Matsumoto M, Kamura T, Murayama M, Chui DH, Planel E, Takahashi R, Nakayama KI, Takashima A.. U-box protein carboxyl terminus of Hsc70-interacting protein (CHIP) mediates poly-ubiquitylation preferentially on four-repeat Tau and is involved in neurodegeneration of tauopathy. J Neurochem, 2004 , 91(2): 299-307.
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