Tau蛋白

Microtubule-associated protein tau; 微管相关蛋白tau
	蛋白质资料库计算机所绘制的连接在P1NI蛋白的结合区域上的MAPT片段
有效结构
PDB	直系同源检索：PDBe, RCSB
PDB查询代码列表
	1I8H, 3FQP, 3OVL, 4E0M, 4E0N, 4E0O, 4GLR
标识
代号	MAPT; DDPAC; FTDP-17; MAPTL; MSTD; MTBT1; MTBT2; PPND; TAU
扩展标识	遗传学：157140 同源基因：74962 ChEMBL: 1293224 GeneCards: MAPT Gene
基因本体论描述
分子功能	· structural constituent of cytoskeleton; · protein binding; · microtubule binding; · SH3 domain binding; · enzyme binding; · protein kinase binding; · apolipoprotein binding; · lipoprotein particle binding;
细胞成分	· cytosol; · microtubule; · microtubule associated complex; · plasma membrane; · axon; · growth cone; · nuclear periphery; · cilium axoneme; · tubulin complex;
生物过程	· microtubule cytoskeleton organization; · neuron migration; · apoptotic process; · cellular component disassembly involved in execution phase of apoptosis; · axonogenesis; · adult walking behavior; · axon cargo transport; · regulation of autophagy; · regulation of microtubule polymerization; · positive regulation of microtubule polymerization; · negative regulation of intracellular transport; · positive regulation of axon extension; · mitochondrion transport along microtubule; · generation of neurons; · regulation of microtubule-based movement;
	Sources: Amigo / QuickGO
RNA表达模式
	更多表达数据
直系同源体
	查; 论; 编;

Tau蛋白（英語：Tau proteins；“Tau”为“Tubulin associated unit”即“微管蛋白相关单位”的缩写），又譯濤蛋白^[1]。是一种微管相关蛋白，在中枢神经系统的神经元非常丰富而少见于其它细胞，在中枢神经系统的星形胶质细胞和少突胶质细胞中表达量也很低^[2]。tau蛋白有缺陷并不再正常稳定微管时，可导致神经系统病变和失智症，如阿兹海默病。

tau蛋白的多种蛋白异型体是由单个基因（人类基因组中为MAPT，microtubule-associated protein tau，微管相关蛋白tau）mRNA的選擇性剪接而形成的^[3]^[4]。1975年，它们由Marc Kirschner在普林斯顿大学的实验室中发现^[5]。

功能[编辑]

tau蛋白是一种高度可溶的微管相关蛋白（MAP）。与非神经元细胞相较，人体内tau更多地在神经元内发现。tau蛋白的主要功能之一是维持轴突微管的稳定性。而其它神经系统中的MAPs家族蛋白也有着相似的功能，这体现在tau敲除的小鼠并没有发现其脑组织的发育受到影响。这可能是在tau缺失后，其它MAPs家族蛋白在神经元内起到代偿tau的作用，从而继续维持轴突微管的稳定，保证脑功能的正常运作。^[6] tau并不在树突发挥功能，而主要作用在轴突远端维持微管的稳定性和必要的灵活性。这与MAP6蛋白（位于轴突近端固定微管）与MAP2（主要维持树突的稳定性）的功能相对。

Tau蛋白与微管蛋白（Tubulin）相互作用以稳定微管，同时驱动Tubulin在微管内组装。Tau蛋白通过异构和磷酸化控制微管的稳定性。

结构[编辑]

六tau蛋白异构体存在于人类脑部组织中，以在结合区域中的编号为标识。其中三个异构体拥有三个结合区域，其余三个异构体则有四个。此结合区域位于该蛋白的羟基末端并带有正电（可与带负电的微管结合）。而带有四个结合区域的异构体有更好的稳定微管的功能。此异构体则为tau基因的2、3和10号外显子被选择性剪切的产物。

tau蛋白可视为一个在最长的tau蛋白异构体上拥有79个丝氨酸和苏氨酸磷酸化位点的磷酸蛋白。有报道称磷酸蛋白在普通tau蛋白的这些位点上的数量已达到30个左右。

磷酸蛋白同时也受激酶宿主的控制，包括PKN（丝氨酸/苏氨酸蛋白激酶）。当PKN被激活，便会磷酸化tau蛋白从而造成微管组织破坏。

tau蛋白的磷酸蛋白也被先天性地控制。例如婴儿中枢神经系统的tau蛋白的磷酸化程度比成人的更高。而所有异构体中的磷酸化程度由于磷酸酶的作用会随着人年龄的增长而减弱。比如激酶，磷酸酶也在对这个tau蛋白的磷酸蛋白的调节中起到作用。

基因[编辑]

临床意义[编辑]

tau蛋白（tau包含物，pTau）的过度磷酸化（英语：Hyperphosphorylation）可导致配对的螺旋丝和直丝的缠结的自组装，其参与阿茲海默症，额颞叶痴呆，和其他tau蛋白病的发病机理^[7]。

脑损伤[编辑]

相互作用[编辑]

另见[编辑]

Tau蛋白病变，一类与tau蛋白积累有关的疾病
慢性創傷性腦病變 (Chronic traumatic encephalopathy, CTE)
拳击员痴呆
阿兹海默病
皮质基地变性
Template:进行性核上性麻痹
蛋白质构象病
皮克氏病
17号染色体额颞叶痴呆症和帕金森氏症
朊病毒

参考文献[编辑]

^ 楊雨哲, 孫承洲. 阿茲海默症的成因及治療 30 (3). 2014-09-30 [2015-01-23]. ISSN 2220-6493. （原始内容存档于2015-01-23）.
^ Shin RW, Iwaki T, Kitamoto T, Tateishi J. Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues. Lab. Invest. May 1991, 64 (5): 693–702. PMID 1903170.
^ Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. U.S.A. June 1988, 85 (11): 4051–5. PMC 280359 . PMID 3131773. doi:10.1073/pnas.85.11.4051.
^ Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. October 1989, 3 (4): 519–26. PMID 2484340. doi:10.1016/0896-6273(89)90210-9.
^ Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. U.S.A. May 1975, 72 (5): 1858–62. PMC 432646 . PMID 1057175. doi:10.1073/pnas.72.5.1858.
^ Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. June 1994, 369 (6480): 488–91. PMID 8202139. doi:10.1038/369488a0.
^ Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. U.S.A. June 2001, 98 (12): 6923–8. PMC 34454 . PMID 11381127. doi:10.1073/pnas.121119298.

进一步阅读[编辑]

Goedert M, Crowther RA, Garner CC. Molecular characterization of microtubule-associated proteins tau and MAP2. Trends Neurosci. 1991, 14 (5): 193–9. PMID 1713721. doi:10.1016/0166-2236(91)90105-4.
Morishima-Kawashima M, Hasegawa M, Takio K; et al. Hyperphosphorylation of tau in PHF. Neurobiol. Aging. 1995, 16 (3): 365–71; discussion 371–80. PMID 7566346. doi:10.1016/0197-4580(95)00027-C.
Heutink P. Untangling tau-related dementia. Hum. Mol. Genet. 2000, 9 (6): 979–86. PMID 10767321. doi:10.1093/hmg/9.6.979.
Goedert M, Spillantini MG. Tau mutations in frontotemporal dementia FTDP-17 and their relevance for Alzheimer's disease. Biochim. Biophys. Acta. 2000, 1502 (1): 110–21. PMID 10899436. doi:10.1016/S0925-4439(00)00037-5.
Morishima-Kawashima M, Ihara Y. [Recent advances in Alzheimer's disease]. Seikagaku. 2002, 73 (11): 1297–307. PMID 11831025.
Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. Mol. Neurobiol. 2002, 24 (1–3): 87–97. PMID 11831556. doi:10.1385/MN:24:1-3:087.
Ingram EM, Spillantini MG. Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends in molecular medicine. 2003, 8 (12): 555–62. PMID 12470988. doi:10.1016/S1471-4914(02)02440-1.
Pickering-Brown S. The tau gene locus and frontotemporal dementia. Dementia and geriatric cognitive disorders. 2004, 17 (4): 258–60. PMID 15178931. doi:10.1159/000077149.
van Swieten JC, Rosso SM, van Herpen E; et al. Phenotypic variation in frontotemporal dementia and parkinsonism linked to chromosome 17. Dementia and geriatric cognitive disorders. 2004, 17 (4): 261–4. PMID 15178932. doi:10.1159/000077150.
Kowalska A, Jamrozik Z, Kwieciński H. Progressive supranuclear palsy--parkinsonian disorder with tau pathology. Folia neuropathologica / Association of Polish Neuropathologists and Medical Research Centre, Polish Academy of Sciences. 2004, 42 (2): 119–23. PMID 15266787.
Rademakers R, Cruts M, van Broeckhoven C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum. Mutat. 2005, 24 (4): 277–95. PMID 15365985. doi:10.1002/humu.20086.
Lee HG, Perry G, Moreira PI; et al. Tau phosphorylation in Alzheimer's disease: pathogen or protector?. Trends in molecular medicine. 2005, 11 (4): 164–9. PMID 15823754. doi:10.1016/j.molmed.2005.02.008.
Hardy J, Pittman A, Myers A; et al. Evidence suggesting that Homo neanderthalensis contributed the H2 MAPT haplotype to Homo sapiens. Biochem. Soc. Trans. 2005, 33 (Pt 4): 582–5. PMID 16042549. doi:10.1042/BST0330582.
Deutsch SI, Rosse RB, Lakshman RM. Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2007, 30 (8): 1369–80. PMID 16793187. doi:10.1016/j.pnpbp.2006.04.007.
Williams DR. Tauopathies: classification and clinical update on neurodegenerative diseases associated with microtubule-associated protein tau. Internal medicine journal. 2006, 36 (10): 652–60. PMID 16958643. doi:10.1111/j.1445-5994.2006.01153.x.
Pittman AM, Fung HC, de Silva R. Untangling the tau gene association with neurodegenerative disorders. Hum. Mol. Genet. 15. 2006,. Spec No 2 (Review Issue 2): R188–95. PMID 16987883. doi:10.1093/hmg/ddl190.
Roder HM, Hutton ML. Microtubule-associated protein tau as a therapeutic target in neurodegenerative disease. Expert Opin. Ther. Targets. 2007, 11 (4): 435–42. PMID 17373874. doi:10.1517/14728222.11.4.435.
van Swieten J, Spillantini MG. Hereditary frontotemporal dementia caused by Tau gene mutations. Brain Pathol. 2007, 17 (1): 63–73. PMID 17493040. doi:10.1111/j.1750-3639.2007.00052.x.
Caffrey TM, Wade-Martins R. Functional MAPT haplotypes: bridging the gap between genotype and neuropathology. Neurobiol. Dis. 2007, 27 (1): 1–10. PMC 2801069 . PMID 17555970. doi:10.1016/j.nbd.2007.04.006.
Delacourte A. Tauopathies: recent insights into old diseases. Folia Neuropathol. 2005, 43 (4): 244–57. PMID 16416389.
Hirokawa N, Shiomura Y, Okabe S. Tau proteins: the molecular structure and mode of binding on microtubules. J. Cell Biol. October 1988, 107 (4): 1449–59. PMC 2115262 . PMID 3139677. doi:10.1083/jcb.107.4.1449.

外部链接[编辑]

醫學主題詞表（MeSH）：tau+Proteins
GeneReviews/NCBI/NIH/UW entry on MAPT-Related Disorders（页面存档备份，存于互联网档案馆）
MR scans of variant CJD CSF Tau positive man

[1] 楊雨哲, 孫承洲. 阿茲海默症的成因及治療 30 (3). 2014-09-30 [2015-01-23]. ISSN 2220-6493. （原始内容存档于2015-01-23）.

[pmid1903170-2] Shin RW, Iwaki T, Kitamoto T, Tateishi J. Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues. Lab. Invest. May 1991, 64 (5): 693–702. PMID 1903170.

[pmid3131773-3] Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. U.S.A. June 1988, 85 (11): 4051–5. PMC 280359 . PMID 3131773. doi:10.1073/pnas.85.11.4051.

[pmid2484340-4] Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron. October 1989, 3 (4): 519–26. PMID 2484340. doi:10.1016/0896-6273(89)90210-9.

[pmid1057175-5] Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. U.S.A. May 1975, 72 (5): 1858–62. PMC 432646 . PMID 1057175. doi:10.1073/pnas.72.5.1858.

[pmid8202139-6] Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T, Sato-Yoshitake R, Takei Y, Noda T, Hirokawa N. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. June 1994, 369 (6480): 488–91. PMID 8202139. doi:10.1038/369488a0.

[pmid11381127-7] Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. U.S.A. June 2001, 98 (12): 6923–8. PMC 34454 . PMID 11381127. doi:10.1073/pnas.121119298.

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