| Structural highlightsDiseaseTAU_HUMAN Note=In Alzheimer disease, the neuronal cytoskeleton in the brain is progressively disrupted and replaced by tangles of paired helical filaments (PHF) and straight filaments, mainly composed of hyperphosphorylated forms of TAU (PHF-TAU or AD P-TAU). O-GlcNAcylation is greatly reduced in Alzheimer disease brain cerebral cortex leading to an increase in TAU/MAPT phosphorylations.[1] [2] [3] Defects in MAPT are a cause of frontotemporal dementia (FTD) [MIM:600274; also called frontotemporal dementia (FTD), pallido-ponto-nigral degeneration (PPND) or historically termed Pick complex. This form of frontotemporal dementia is characterized by presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.[4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] Defects in MAPT are a cause of Pick disease of the brain (PIDB) [MIM:172700. It is a rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration.[29] [30] [31] [32] [33] [34] [35] [36] Note=Defects in MAPT are a cause of corticobasal degeneration (CBD). It is marked by extrapyramidal signs and apraxia and can be associated with memory loss. Neuropathologic features may overlap Alzheimer disease, progressive supranuclear palsy, and Parkinson disease.[37] [38] [39] Defects in MAPT are a cause of progressive supranuclear palsy type 1 (PSNP1) [MIM:601104; also abbreviated as PSP and also known as Steele-Richardson-Olszewski syndrome. PSNP1 is characterized by akinetic-rigid syndrome, supranuclear gaze palsy, pyramidal tract dysfunction, pseudobulbar signs and cognitive capacities deterioration. Neurofibrillary tangles and gliosis but no amyloid plaques are found in diseased brains. Most cases appear to be sporadic, with a significant association with a common haplotype including the MAPT gene and the flanking regions. Familial cases show an autosomal dominant pattern of transmission with incomplete penetrance; genetic analysis of a few cases showed the occurrence of tau mutations, including a deletion of Asn-613.[40] [41] [42] [43] [44] [45] [46] [47] [48] Defects in MAPT are a cause of Parkinson-dementia syndrome (PARDE) [MIM:260540. A syndrome characterized by parkinsonism tremor, rigidity, dementia, ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration occurs in the hippocampus, basal ganglia and brainstem nuclei.[49] [50] [51]
FunctionTAU_HUMAN Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization.[52]
Publication Abstract from PubMed
Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 A resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-beta/beta-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases.
Cryo-EM structures of tau filaments from Alzheimer's disease.,Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW Nature. 2017 Jul 13;547(7662):185-190. doi: 10.1038/nature23002. Epub 2017 Jul 5. PMID:28678775[53]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See AlsoReferences
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- ↑ 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. 1989 Oct;3(4):519-26. PMID:2484340
- ↑ Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PMID:14517953 doi:10.1002/humu.10269
- ↑ Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009 Jul;132(Pt 7):1820-32. doi: 10.1093/brain/awp099. Epub 2009 May 18. PMID:19451179 doi:10.1093/brain/awp099
- ↑ 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. 1989 Oct;3(4):519-26. PMID:2484340
- ↑ Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PMID:14517953 doi:10.1002/humu.10269
- ↑ Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Andreadis A, Wiederholt WC, Raskind M, Schellenberg GD. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998 Jun;43(6):815-25. PMID:9629852 doi:10.1002/ana.410430617
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- ↑ Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009 Jul;132(Pt 7):1820-32. doi: 10.1093/brain/awp099. Epub 2009 May 18. PMID:19451179 doi:10.1093/brain/awp099
- ↑ 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. 1989 Oct;3(4):519-26. PMID:2484340
- ↑ Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PMID:14517953 doi:10.1002/humu.10269
- ↑ Murrell JR, Spillantini MG, Zolo P, Guazzelli M, Smith MJ, Hasegawa M, Redi F, Crowther RA, Pietrini P, Ghetti B, Goedert M. Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol. 1999 Dec;58(12):1207-26. PMID:10604746
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- ↑ Rizzini C, Goedert M, Hodges JR, Smith MJ, Jakes R, Hills R, Xuereb JH, Crowther RA, Spillantini MG. Tau gene mutation K257T causes a tauopathy similar to Pick's disease. J Neuropathol Exp Neurol. 2000 Nov;59(11):990-1001. PMID:11089577
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- ↑ Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009 Jul;132(Pt 7):1820-32. doi: 10.1093/brain/awp099. Epub 2009 May 18. PMID:19451179 doi:10.1093/brain/awp099
- ↑ 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. 1989 Oct;3(4):519-26. PMID:2484340
- ↑ Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PMID:14517953 doi:10.1002/humu.10269
- ↑ Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009 Jul;132(Pt 7):1820-32. doi: 10.1093/brain/awp099. Epub 2009 May 18. PMID:19451179 doi:10.1093/brain/awp099
- ↑ 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. 1989 Oct;3(4):519-26. PMID:2484340
- ↑ Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PMID:14517953 doi:10.1002/humu.10269
- ↑ Higgins JJ, Adler RL, Loveless JM. Mutational analysis of the tau gene in progressive supranuclear palsy. Neurology. 1999 Oct 22;53(7):1421-4. PMID:10534245
- ↑ Pastor P, Pastor E, Carnero C, Vela R, Garcia T, Amer G, Tolosa E, Oliva R. Familial atypical progressive supranuclear palsy associated with homozigosity for the delN296 mutation in the tau gene. Ann Neurol. 2001 Feb;49(2):263-7. PMID:11220749
- ↑ Poorkaj P, Muma NA, Zhukareva V, Cochran EJ, Shannon KM, Hurtig H, Koller WC, Bird TD, Trojanowski JQ, Lee VM, Schellenberg GD. An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol. 2002 Oct;52(4):511-6. PMID:12325083 doi:10.1002/ana.10340
- ↑ Rossi G, Gasparoli E, Pasquali C, Di Fede G, Testa D, Albanese A, Bracco F, Tagliavini F. Progressive supranuclear palsy and Parkinson's disease in a family with a new mutation in the tau gene. Ann Neurol. 2004 Mar;55(3):448. PMID:14991829 doi:10.1002/ana.20006
- ↑ Oliva R, Pastor P. Tau gene delN296 mutation, Parkinson's disease, and atypical supranuclear palsy. Ann Neurol. 2004 Mar;55(3):448-9. PMID:14991828 doi:10.1002/ana.20025
- ↑ Ros R, Thobois S, Streichenberger N, Kopp N, Sanchez MP, Perez M, Hoenicka J, Avila J, Honnorat J, de Yebenes JG. A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy. Arch Neurol. 2005 Sep;62(9):1444-50. PMID:16157753 doi:62/9/1444
- ↑ Liu F, Shi J, Tanimukai H, Gu J, Gu J, Grundke-Iqbal I, Iqbal K, Gong CX. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer's disease. Brain. 2009 Jul;132(Pt 7):1820-32. doi: 10.1093/brain/awp099. Epub 2009 May 18. PMID:19451179 doi:10.1093/brain/awp099
- ↑ 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. 1989 Oct;3(4):519-26. PMID:2484340
- ↑ Rademakers R, Dermaut B, Peeters K, Cruts M, Heutink P, Goate A, Van Broeckhoven C. Tau (MAPT) mutation Arg406Trp presenting clinically with Alzheimer disease does not share a common founder in Western Europe. Hum Mutat. 2003 Nov;22(5):409-11. PMID:14517953 doi:10.1002/humu.10269
- ↑ Yoshida H, Goedert M. Phosphorylation of microtubule-associated protein tau by AMPK-related kinases. J Neurochem. 2012 Jan;120(1):165-76. doi: 10.1111/j.1471-4159.2011.07523.x. Epub , 2011 Nov 11. PMID:21985311 doi:10.1111/j.1471-4159.2011.07523.x
- ↑ Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M, Scheres SHW. Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. doi: 10.1038/nature23002. Epub 2017 Jul 5. PMID:28678775 doi:http://dx.doi.org/10.1038/nature23002
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