Regulation of human MAPT gene expression

Molecular Neurodegeneration

Bruno Lefebvre¹  Nicolas Sergeant¹  Luc Buée¹  Marie-Laure Caillet-Boudin¹ 

[1] Univ. Lille, UMR-S 1172, Inserm, CHU, Lille, 59000, France

关键词: Tau splicing;    Tau promoter;    Tau haplotype;    CpG islands;    Repeat sequences;    Alzheimer’s disease;    MAPT;    Tauopathy;    Tau;   

Others  :  1219846
DOI  :  10.1186/s13024-015-0025-8

 received in 2015-04-21, accepted in 2015-06-30,  发布年份 2015

【 摘 要 】

The number of known pathologies involving deregulated Tau expression/metabolism is increasing. Indeed, in addition to tauopathies, which comprise approximately 30 diseases characterized by neuronal aggregation of hyperphosphorylated Tau in brain neurons, this protein has also been associated with various other pathologies such as cancer, inclusion body myositis, and microdeletion/microduplication syndromes, suggesting its possible function in peripheral tissues. In addition to Tau aggregation, Tau deregulation can occur at the expression and/or splicing levels, as has been clearly demonstrated in some of these pathologies. Here, we aim to review current knowledge regarding the regulation of human MAPT gene expression at the DNA and RNA levels to provide a better understanding of its possible deregulation. Several aspects, including repeated motifs, CpG island/methylation, and haplotypes at the DNA level, as well as the key regions involved in mRNA expression and stability and the splicing patterns of different mRNA isoforms at the RNA level, will be discussed.

【 授权许可】

   
2015 Caillet-Boudin et al.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975; 72:1858-1862.
• [2]Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007; 8:663-672.
• [3]Sergeant N, Delacourte A, Buee L. Tau protein as a differential biomarker of tauopathies. Biochim Biophys Acta. 1739; 2005:179-197.
• [4]Baird FJ, Bennett CL. Microtubule defects & Neurodegeneration. J Genet Syndr Gene Ther. 2013; 4:203.
• [5]Scholz T, Mandelkow E. Transport and diffusion of Tau protein in neurons. Cell Mol Life Sci. 2014; 71:3139-50.
• [6]Boehm J. A ‘danse macabre’: tau and Fyn in STEP with amyloid beta to facilitate induction of synaptic depression and excitotoxicity. Eur J Neurosci. 2013; 37:1925-1930.
• [7]Spires-Jones TL, Hyman BT. The Intersection of Amyloid Beta and Tau at Synapses in Alzheimer’s Disease. Neuron. 2014; 82:756-771.
• [8]Sultan A, Nesslany F, Violet M, Begard S, Loyens A, Talahari S, et al. Nuclear tau, a key player in neuronal DNA protection. J Biol Chem. 2011;286:4566–75.
• [9]Violet M, Delattre L, Tardivel M, Sultan A, Chauderlier A, Caillierez R, et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci. 2014;8:84.
• [10]Schraen-Maschke S, Sergeant N, Dhaenens CM, Bombois S, Deramecourt V, Caillet-Boudin ML, et al. Tau as a biomarker of neurodegenerative diseases. Biomark Med. 2008;2:363–84.
• [11]Goedert M, Ghetti B, Spillantini MG. Frontotemporal dementia: implications for understanding Alzheimer disease. Cold Spring Harb Perspect Med. 2012; 2:a006254.
• [12]Kon T, Mori F, Tanji K, Miki Y, Tomiyama M, Baba M, et al. Abnormal tau deposition in neurons, but not in glial cells in the cerebral tissue surrounding arteriovenous malformation. Neuropathology. 2012;32:267–71.
• [13]Brat DJ, Gearing M, Goldthwaite PT, Wainer BH, Burger PC. Tau-associated neuropathology in ganglion cell tumours increases with patient age butappears unrelated to ApoE genotype. Neuropathol Appl Neurobiol. 2001;27:197–205.
• [14]Oberc-Greenwood MA, McKeever PE, Kornblith PL, Smith BH. A human ganglioglioma containing paired helical filaments. Hum Pathol. 1984; 15:834-838.
• [15]Ikeda K, Akiyama H, Kondo H, Arai T, Arai N, Yagishita S. Numerous glial fibrillary tangles in oligodendroglia in cases of subacute sclerosing panencephalitis with neurofibrillary tangles. Neurosci Lett. 1995; 194:133-135.
• [16]Hof PR, Charpiot A, Delacourte A, Buee L, Purohit D, Perl DP, et al. Distribution of neurofibrillary tangles and senile plaques in the cerebral cortex in postencephalitic parkinsonism. Neurosci Lett. 1992;139:10–4.
• [17]Moran MA, Probst A, Navarro C, Gomez-Ramos P. Alzheimer’s disease-type neurofibrillary degeneration in verrucose dysplasias of the cerebral cortex. Acta Neuropathol. 1995; 90:356-365.
• [18]Ball MJ, Nuttall K. Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down Syndrome: quantitative comparison with Alzheimer dementia. Ann Neurol. 1980; 7:462-465.
• [19]Vermersch P, Sergeant N, Ruchoux MM, Hofmann-Radvanyi H, Wattez A, Petit H, et al. Specific tau variants in the brains of patients with myotonic dystrophy. Neurology. 1996;47:711–7.
• [20]Hirano A, Malamud N, Kurland LT. Parkinsonism-dementia complex, an endemic disease on the island of Guam. II. Pathological features. Brain. 1961; 84:662-679.
• [21]Hof PR, Bouras C, Buee L, Delacourte A, Perl DP, Morrison JH. Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer’s disease cases. Acta Neuropathol. 1992; 85:23-30.
• [22]Tokuda T, Ikeda S, Yanagisawa N, Ihara Y, Glenner GG. Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol. 1991; 82:280-285.
• [23]Fernandez-Nogales M, Cabrera JR, Santos-Galindo M, Hoozemans JJ, Ferrer I, Rozemuller AJ, et al. Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat Med. 2014;20:881–5.
• [24]Caillet-Boudin ML, Fernandez-Gomez FJ, Tran H, Dhaenens CM, Buee L, Sergeant N. Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy. Front Mol Neurosci. 2014; 6:57.
• [25]Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol. 2009;117:15–8.
• [26]Shi J, Shaw CL, Du Plessis D, Richardson AM, Bailey KL, Julien C, et al. Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation. Acta Neuropathol. 2005;110:501–12.
• [27]Zhukareva V, Vogelsberg-Ragaglia V, Van Deerlin VM, Bruce J, Shuck T, Grossman M, et al. Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia. Ann Neurol. 2001;49:165–75.
• [28]Lattante S, Rouleau GA, Kabashi E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum Mutat. 2013; 34:812-826.
• [29]Dubourg C, Sanlaville D, Doco-Fenzy M, Le Caignec C, Missirian C, Jaillard S, et al. Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation. Eur J Med Genet. 2011;54:144–51.
• [30]Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ, Schwartz M. A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet. 2007; 50:256-263.
• [31]Sharkey FH, Morrison N, Murray R, Iremonger J, Stephen J, Maher E, et al. 17q21.31 microdeletion syndrome: further expanding the clinical phenotype. Cytogenet Genome Res. 2009;127:61–6.
• [32]Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet. 2006;38:1032–7.
• [33]Desikan RS, Schork AJ, Wang Y, Witoelar A, Sharma M, McEvoy LK, Holland D, Brewer JB, Chen CH, Thompson WK, et al.: Genetic overlap between Alzheimer’s disease and Parkinson's disease at the MAPT locus. Mol Psychiatry 2015, doi: 10.1038/mp.2015.6
• [34]Edwards TL, Scott WK, Almonte C, Burt A, Powell EH, Beecham GW, et al. Genome-wide association study confirms SNPs in SNCA and the MAPT region as common risk factors for Parkinson disease. Ann Hum Genet. 2010;74:97–109.
• [35]Simon-Sanchez J, Schulte C, Bras JM, Sharma M, Gibbs JR, Berg D, et al. Genome-wide association study reveals genetic risk underlying Parkinson's disease. Nat Genet. 2009;41:1308–12.
• [36]Askanas V, Engel WK, Bilak M, Alvarez RB, Selkoe DJ. Twisted tubulofilaments of inclusion body myositis muscle resemble paired helical filaments of Alzheimer brain and contain hyperphosphorylated tau. Am J Pathol. 1994; 144:177-187.
• [37]Maurage CA, Bussiere T, Sergeant N, Ghesteem A, Figarella-Branger D, Ruchoux MM, et al. Tau aggregates are abnormally phosphorylated in inclusion body myositis and have an immunoelectrophoretic profile distinct from other tauopathies. Neuropathol Appl Neurobiol. 2004;30:624–34.
• [38]Matrone MA, Whipple RA, Thompson K, Cho EH, Vitolo MI, Balzer EM, et al. Metastatic breast tumors express increased tau, which promotes microtentacle formation and the reattachment of detached breast tumor cells. Oncogene. 2010;29:3217–27.
• [39]Pusztai L, Jeong JH, Gong Y, Ross JS, Kim C, Paik S, et al. Evaluation of microtubule-associated protein-Tau expression as a prognostic and predictive marker in the NSABP-B 28 randomized clinical trial. J Clin Oncol. 2009;27:4287–92.
• [40]Cirak Y, Sarsik B, Cakar B, Sen S, Simsir A, Uslu R. Predictive and prognostic values of Tau and BubR1 protein in prostate cancer and their relationship to the Gleason score. Med Oncol. 2013; 30:526.
• [41]Souter S, Lee G. Microtubule-associated protein tau in human prostate cancer cells: isoforms, phosphorylation, and interactions. J Cell Biochem. 2009; 108:555-564.
• [42]Fekete T, Raso E, Pete I, Tegze B, Liko I, Munkacsy G, et al. Meta-analysis of gene expression profiles associated with histological classification and survival in 829 ovarian cancer samples. Int J Cancer. 2012;131:95–105.
• [43]Smoter M, Bodnar L, Grala B, Stec R, Zieniuk K, Kozlowski W, et al. Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy. J Exp Clin Cancer Res. 2013;32:25.
• [44]Wosnitzer MS, Domingo-Domenech J, Castillo-Martin M, Ritch C, Mansukhani M, Petrylack DP, et al. Predictive value of microtubule associated proteins tau and stathmin in patients with nonmuscleinvasive bladder cancer receiving adjuvant intravesical taxane therapy. J Urol. 2011;186:2094–100.
• [45]Wu H, Huang M, Lu M, Zhu W, Shu Y, Cao P, et al. Regulation of microtubule-associated protein tau (MAPT) by miR-34c-5p determines the chemosensitivity of gastric cancer to paclitaxel. Cancer Chemother Pharmacol. 2013;71:1159–71.
• [46]Wang K, Deng QT, Liao N, Zhang GC, Liu YH, Xu FP, et al. Tau expression correlated with breast cancer sensitivity to taxanes-based neoadjuvant chemotherapy. Tumour Biol. 2013;34:33–8.
• [47]Andre F, Hatzis C, Anderson K, Sotiriou C, Mazouni C, Mejia J, et al. Microtubule-associated protein-tau is a bifunctional predictor ofendocrine sensitivity and chemotherapy resistance in estrogen receptor-positive breast cancer. Clin Cancer Res. 2007;13:2061–7.
• [48]Baquero MT, Lostritto K, Gustavson MD, Bassi KA, Appia F, Camp RL, et al. Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts. Breast Cancer Res. 2011;13:R85.
• [49]Im S, Yoo C, Jung JH, Jeon YW, Suh YJ, Lee YS, et al. Microtubule-Associated Protein Tau, alpha-Tubulin and betaIII-Tubulin Expression in Breast Cancer. Korean J Pathol. 2013;47:534–40.
• [50]Irshad S, Gillett C, Pinder SE, A'Hern RP, Dowsett M, Ellis IO, et al. Assessment of microtubule-associated protein (MAP)-Tau expression as a predictive and prognostic marker in TACT; a trial assessing substitution of sequential docetaxel for FEC as adjuvant chemotherapy for early breast cancer. Breast Cancer Res Treat. 2014;144:331–41.
• [51]Li ZH, Xiong QY, Tu JH, Gong Y, Qiu W, Zhang HQ, et al. Tau proteins expressions in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy. Med Oncol. 2013;30:591.
• [52]Mimori K, Sadanaga N, Yoshikawa Y, Ishikawa K, Hashimoto M, Tanaka F, et al. Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment. Br J Cancer. 2006;94:1894–7.
• [53]Spicakova T, O'Brien MM, Duran GE, Sweet-Cordero A, Sikic BI. Expression and silencing of the microtubule-associated protein Tau in breast cancer cells. Mol Cancer Ther. 2010; 9:2970-2981.
• [54]Steffensen KD, Smoter M, Waldstrom M, Grala B, Bodnar L, Stec R, et al. Resistance to first line platinum paclitaxel chemotherapy in serous epithelial ovarian cancer: the prediction value of ERCC1 and Tau expression. Int J Oncol. 2014;44:1736–44.
• [55]Wang Q, Wang N, Shao G, Qian J, Shen D, Fei Y, et al. Relationship between gastric cancer tau protein expression and paclitaxel sensitivity. Pathol Oncol Res. 2013;19:429–35.
• [56]Won HS, Lee KE, Sung SH, Choi MY, Jo JY, Nam EM, et al. Topoisomerase II alpha and microtubule-associated protein-tau as a predictive marker in axillary lymph node positive breast cancer. Tumori. 2014;100:80–6.
• [57]Andreadis A. Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases. Biochim Biophys Acta. 1739; 2005:91-103.
• [58]Andreadis A. Tau splicing and the intricacies of dementia. J Cell Physiol. 2012; 227:1220-1225.
• [59]Borroni B, Agosti C, Magnani E, Di Luca M, Padovani A. Genetic bases of Progressive Supranuclear Palsy: the MAPT tau disease. Curr Med Chem. 2011; 18:2655-2660.
• [60]Caffrey TM, Wade-Martins R. Functional MAPT haplotypes: bridging the gap between genotype and neuropathology. Neurobiol Dis. 2007; 27:1-10.
• [61]Niblock M, Gallo JM. Tau alternative splicing in familial and sporadic tauopathies. Biochem Soc Trans. 2012; 40:677-680.
• [62]Wang C, Huang S. Nuclear function of Alus. Nucleus. 2014; 5:131-137.
• [63]Levy A, Sela N, Ast G. TranspoGene and microTranspoGene: transposed elements influence on the transcriptome of seven vertebrates and invertebrates. Nucleic Acids Res. 2008; 36:D47-52.
• [64]Maloney B, Lahiri DK. Structural and functional characterization of H2 haplotype MAPT promoter: unique neurospecific domains and a hypoxia-inducible element would enhance rationally targeted tauopathy research for Alzheimer's disease. Gene. 2012; 501:63-78.
• [65]Sadot E, Heicklen-Klein A, Barg J, Lazarovici P, Ginzburg I. Identification of a tau promoter region mediating tissue-specific-regulated expression in PC12 cells. J Mol Biol. 1996; 256:805-812.
• [66]Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860–921.
• [67]Yanez-Cuna JO, Arnold CD, Stampfel G, Boryn LM, Gerlach D, Rath M, et al. Dissection of thousands of cell type-specific enhancers identifies dinucleotide repeat motifs as general enhancer features. Genome Res. 2014;24:1147–56.
• [68]Mohan A. Goodwin M. Swanson MS, RNA-protein interactions in unstable microsatellite diseases. Brain Res; 2014.
• [69]Wojciechowska M, Krzyzosiak WJ. Cellular toxicity of expanded RNA repeats: focus on RNA foci. Hum Mol Genet. 2011; 20:3811-3821.
• [70]Benson G. Tandem repeats finder: a program to analyze DNA sequences. Nucleic Acids Res. 1999; 27:573-580.
• [71]Conrad C, Andreadis A, Trojanowski JQ, Dickson DW, Kang D, Chen X, et al. Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol. 1997;41:277–81.
• [72]Conrad C, Amano N, Andreadis A, Xia Y, Namekataf K, Oyama F, et al. Differences in a dinucleotide repeat polymorphism in the tau gene between Caucasian and Japanese populations: implication for progressive supranuclear palsy. Neurosci Lett. 1998;250:135–7.
• [73]Holzer M, Craxton M, Jakes R, Arendt T, Goedert M. Tau gene (MAPT) sequence variation among primates. Gene. 2004; 341:313-322.
• [74]Poorkaj P, Kas A, D'Souza I, Zhou Y, Pham Q, Stone M, et al. A genomic sequence analysis of the mouse and human microtubule-associated protein tau. Mamm Genome. 2001;12:700–12.
• [75]Andreadis A, Brown WM, Kosik KS. Structure and novel exons of the human tau gene. Biochemistry. 1992; 31:10626-10633.
• [76]Gardiner-Garden M, Frommer M. CpG islands in vertebrate genomes. J Mol Biol. 1987; 196:261-282.
• [77]Andreadis A, Wagner BK, Broderick JA, Kosik KS. A tau promoter region without neuronal specificity. J Neurochem. 1996; 66:2257-2263.
• [78]Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.
• [79]Karolchik D, Barber GP, Casper J, Clawson H, Cline MS, Diekhans M, et al. The UCSC Genome Browser database: 2014 update. Nucleic Acids Res. 2002;42:D764–770.
• [80]Maunakea AK, Nagarajan RP, Bilenky M, Ballinger TJ, D'Souza C, Fouse SD, et al. Conserved role of intragenic DNA methylation in regulating alternative promoters. Nature. 2010;466:253–7.
• [81]Li LC, Dahiya R. MethPrimer: designing primers for methylation PCRs. Bioinformatics. 2002; 18:1427-1431.
• [82]Coupland KG, Mellick GD, Silburn PA, Mather K, Armstrong NJ, Sachdev PS, et al. DNA methylation of the MAPT gene in Parkinson's disease cohorts and modulation by vitamin E In Vitro. Mov Disord. 2014;29(13):1606–14.
• [83]Iwata A, Nagata K, Hatsuta H, Takuma H, Bundo M, Iwamoto K, et al. Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation. Hum Mol Genet. 2014;23:648–56.
• [84]Barrachina M, Ferrer I. DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain. J Neuropathol Exp Neurol. 2009; 68:880-891.
• [85]Schraen-Maschke S, Dhaenens CM, Delacourte A, Sablonniere B. Microtubule-associated protein tau gene: a risk factor in human neurodegenerative diseases. Neurobiol Dis. 2004; 15:449-460.
• [86]Cruts M, Rademakers R, Gijselinck I, van der Zee J, Dermaut B, de Pooter T, et al. Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum Mol Genet. 2005;14:1753–62.
• [87]Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, et al. A common inversion under selection in Europeans. Nat Genet. 2005;37:129–37.
• [88]Rao PN, Li W, Vissers LE, Veltman JA, Ophoff RA. Recurrent inversion events at 17q21.31 microdeletion locus are linked to the MAPT H2 haplotype. Cytogenet Genome Res. 2010;129:275–9.
• [89]Pittman AM, Myers AJ, Duckworth J, Bryden L, Hanson M, Abou-Sleiman P, et al. The structure of the tau haplotype in controls and in progressive supranuclear palsy. Hum Mol Genet. 2004;13:1267–74.
• [90]Cruchaga C, Vidal-Taboada JM, Ezquerra M, Lorenzo E, Martinez-Lage P, Blazquez M, et al. 5'-Upstream variants of CRHR1 and MAPT genes associated with age at onset in progressive supranuclear palsy and cortical basaldegeneration. Neurobiol Dis. 2009;33:164–70.
• [91]Ezquerra M, Pastor P, Gaig C, Vidal-Taboada JM, Cruchaga C, Munoz E, et al. Different MAPT haplotypes are associated with Parkinson's disease and progressive supranuclear palsy. Neurobiol Aging. 2011;32:547. e511-546.
• [92]Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC, et al. The H1c haplotype at the MAPT locus is associated with Alzheimer's disease. Hum Mol Genet. 2005;14:2399–404.
• [93]Pittman AM, Myers AJ, Abou-Sleiman P, Fung HC, Kaleem M, Marlowe L, et al. Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration. J Med Genet. 2005;42:837–46.
• [94]Santa-Maria I, Haggiagi A, Liu X, Wasserscheid J, Nelson PT, Dewar K, et al. The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathol. 2012;124:693–704.
• [95]Sobrido MJ, Abu-Khalil A, Weintraub S, Johnson N, Quinn B, Cummings JL, et al. Possible association of the tau H1/H1 genotype with primary progressive aphasia. Neurology. 2003;60:862–4.
• [96]Tobin JE, Latourelle JC, Lew MF, Klein C, Suchowersky O, Shill HA, et al. Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study. Neurology. 2008;71:28–34.
• [97]Togo T, Sahara N, Yen SH, Cookson N, Ishizawa T, Hutton M, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol. 2002;61:547–56.
• [98]Sobrido MJ, Miller BL, Havlioglu N, Zhukareva V, Jiang Z, Nasreddine ZS, et al. Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia. Arch Neurol. 2003;60:698–702.
• [99]Russ C, Lovestone S, Baker M, Pickering-Brown SM, Andersen PM, Furlong R, et al. The extended haplotype of the microtubule associated protein tau gene is not associated with Pick's disease. Neurosci Lett. 2001;299:156–8.
• [100]Li Y, Chen JA, Sears RL, Gao F, Klein ED, Karydas A, et al. An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy. PLoS Genet. 2014;10:e1004211.
• [101]Myers AJ, Pittman AM, Zhao AS, Rohrer K, Kaleem M, Marlowe L, et al. The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis. 2007;25:561–70.
• [102]Caffrey TM, Joachim C, Wade-Martins R. Haplotype-specific expression of the N-terminal exons 2 and 3 at the human MAPT locus. Neurobiol Aging. 2008; 29:1923-1929.
• [103]Zhong Q, Congdon EE, Nagaraja HN, Kuret J. Tau isoform composition influences rate and extent of filament formation. J Biol Chem. 2012; 287:20711-20719.
• [104]Hayesmoore JB, Bray NJ, Cross WC, Owen MJ, O'Donovan MC, Morris HR. The effect of age and the H1c MAPT haplotype on MAPT expression in human brain. Neurobiol Aging. 2009; 30:1652-1656.
• [105]Kwok JB, Teber ET, Loy C, Hallupp M, Nicholson G, Mellick GD, et al. Tau haplotypes regulate transcription and are associated with Parkinson's disease. Ann Neurol. 2004;55:329–34.
• [106]Rademakers R, Melquist S, Cruts M, Theuns J, Del-Favero J, Poorkaj P, et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet.2005;14:3281–92.
• [107]Colom-Cadena M, Gelpi E, Marti MJ, Charif S, Dols-Icardo O, Blesa R, et al. MAPT H1 haplotype is associated with enhanced alpha-synuclein deposition in dementia with Lewy bodies. Neurobiol Aging. 2013;34:936–42.
• [108]Compta Y, Parkkinen L, O'Sullivan SS, Vandrovcova J, Holton JL, Collins C, et al. Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important? Brain. 2011;134:1493–505.
• [109]Wider C, Ross OA, Nishioka K, Heckman MG, Vilarino-Guell C, Jasinska-Myga B, et al. An evaluation of the impact of MAPT, SNCA and APOE on the burden of Alzheimer's and Lewy body pathology. J Neurol Neurosurg Psychiatry. 2012;83:424–9.
• [110]Bombois S, Duhamel A, Salleron J, Deramecourt V, Mackowiak MA, Deken V, et al. A new decision tree combining Abeta 1–42 and p-Tau levels inAlzheimer's diagnosis. Curr Alzheimer Res. 2013;10:357–64.
• [111]Kauwe JS, Cruchaga C, Mayo K, Fenoglio C, Bertelsen S, Nowotny P, et al. Variation in MAPT is associated with cerebrospinal fluid tau levels in the presence of amyloid-beta deposition. Proc Natl Acad Sci U S A. 2008;105:8050–4.
• [112]Laws SM, Friedrich P, Diehl-Schmid J, Muller J, Eisele T, Bauml J, et al. Fine mapping of the MAPT locus using quantitative trait analysis identifies possible causal variants in Alzheimer's disease. Mol Psychiatry. 2007;12:510–7.
• [113]Amadoro G, Corsetti V, Sancesario GM, Lubrano A, Melchiorri G, Bernardini S, et al. Cerebrospinal fluid levels of a 20–22 kDa NH2 fragment of human tau provide a novel neuronal injury biomarker in Alzheimer's disease and other dementias. J Alzheimers Dis. 2014;42:211–26.
• [114]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; 3:519-526.
• [115]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. 1988; 85:4051-4055.
• [116]Gu Y, Oyama F, Ihara Y. Tau is widely expressed in rat tissues. J Neurochem. 1996; 67:1235-1244.
• [117]Wei ML, Andreadis A. Splicing of a regulated exon reveals additional complexity in the axonal microtubule-associated protein tau. J Neurochem. 1998; 70:1346-1356.
• [118]Rouzier R, Rajan R, Wagner P, Hess KR, Gold DL, Stec J, et al. Microtubule-associated protein tau: a marker of paclitaxel sensitivity in breast cancer. Proc Natl Acad Sci U S A. 2005;102:8315–20.
• [119]Drubin D, Kobayashi S, Kellogg D, Kirschner M. Regulation of microtubule protein levels during cellular morphogenesis in nerve growth factor-treated PC12 cells. J Cell Biol. 1988; 106:1583-1591.
• [120]Sadot E, Marx R, Barg J, Behar L, Ginzburg I. Complete sequence of 3'-untranslated region of Tau from rat central nervous system. Implications for mRNA heterogeneity. J Mol Biol. 1994; 241:325-331.
• [121]Gao L, Tucker KL, Andreadis A. Transcriptional regulation of the mouse microtubule-associated protein tau. Biochim Biophys Acta. 2005; 1681:175-181.
• [122]Heicklen-Klein A, Ginzburg I. Tau promoter confers neuronal specificity and binds Sp1 and AP-2. J Neurochem. 2000; 75:1408-1418.
• [123]Heicklen-Klein A, Aronov S, Ginzburg I. Tau promoter activity in neuronally differentiated P19 cells. Brain Res. 2000; 874:1-9.
• [124]Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, et al. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci U S A. 2002;99:16899–903.
• [125]Flicek P, Amode MR, Barrell D, Beal K, Billis K, Brent S, et al. Ensembl 2014. Nucleic Acids Res. 2014;42:D749–755.
• [126]Maloney B, Lahiri DK. The Alzheimer's amyloid beta-peptide (Abeta) binds a specific DNA Abeta-interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif. Gene. 2011; 488:1-12.
• [127]Bloom GS. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 2014; 71:505-508.
• [128]Ittner LM, Gotz J. Amyloid-beta and tau--a toxic pas de deux in Alzheimer's disease. Nat Rev Neurosci. 2011; 12:65-72.
• [129]Batut P, Gingeras TR. RAMPAGE: promoter activity profiling by paired-end sequencing of 5'-complete cDNAs. Curr Protoc Mol Biol. 2013; 104:Unit 25B 11.
• [130]Shabalina SA, Ogurtsov AY, Spiridonov NA, Koonin EV. Evolution at protein ends: major contribution of alternative transcription initiation and termination to the transcriptome and proteome diversity in mammals. Nucleic Acids Res. 2014; 42:7132-7144.
• [131]Wang Y, Loomis PA, Zinkowski RP, Binder LI. A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau. J Cell Biol. 1993; 121:257-267.
• [132]Suske G. The Sp-family of transcription factors. Gene. 1999; 238:291-300.
• [133]Farre D, Roset R, Huerta M, Adsuara JE, Rosello L, Alba MM, et al. Identification of patterns in biological sequences at the ALGGEN server: PROMO and MALGEN. Nucleic Acids Res. 2003;31:3651–3.
• [134]Qian W, Liu F. Regulation of alternative splicing of tau exon 10. Neurosci Bull. 2014; 30:367-377.
• [135]Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001; 24:1121-1159.
• [136]Sergeant N, Bretteville A, Hamdane M, Caillet-Boudin ML, Grognet P, Bombois S, et al. Biochemistry of Tau in Alzheimer's disease and related neurological disorders. Expert Rev Proteomics. 2008;5:207–24.
• [137]Leroy O, Wang J, Maurage CA, Parent M, Cooper T, Buee L, et al. Brain-specific change in alternative splicing of Tau exon 6 in myotonic dystrophy type 1. Biochim Biophys Acta. 1762;2006:460–7.
• [138]Goedert M, Spillantini MG, Potier MC, Ulrich J, Crowther RA. Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. EMBO J. 1989; 8:393-399.
• [139]Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013; 12:609-622.
• [140]Goedert M, Spillantini MG, Crowther RA. Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. Proc Natl Acad Sci U S A. 1992; 89:1983-1987.
• [141]Wang J, Tse SW, Andreadis A. Tau exon 6 is regulated by an intricate interplay of trans factors and cis elements, including multiple branch points. J Neurochem. 2007; 100:437-445.
• [142]Luo MH, Leski ML, Andreadis A. Tau isoforms which contain the domain encoded by exon 6 and their role in neurite elongation. J Cell Biochem. 2004; 91:880-895.
• [143]Luo MH, Tse SW, Memmott J, Andreadis A. Novel isoforms of tau that lack the microtubule-binding domain. J Neurochem. 2004; 90:340-351.
• [144]Kanaan NM, Morfini GA, LaPointe NE, Pigino GF, Patterson KR, Song Y, et al. Pathogenic forms of tau inhibit kinesin-dependent axonal transport through a mechanism involving activation of axonal phosphotransferases. J Neurosci. 2011;31:9858–68.
• [145]Lapointe NE, Horowitz PM, Guillozet-Bongaarts AL, Silva A, Andreadis A, Binder LI. Tau 6D and 6P isoforms inhibit polymerization of full-length tau in vitro. Biochemistry. 2009; 48:12290-12297.
• [146]Nelson PT, Stefansson K, Gulcher J, Saper CB. Molecular evolution of tau protein: implications for Alzheimer's disease. J Neurochem. 1996; 67:1622-1632.
• [147]Himmler A. Structure of the bovine tau gene: alternatively spliced transcripts generate a protein family. Mol Cell Biol. 1989; 9:1389-1396.
• [148]Andreadis A, Nisson PE, Kosik KS, Watkins PC. The exon trapping assay partly discriminates against alternatively spliced exons. Nucleic Acids Res. 1993; 21:2217-2221.
• [149]Lau P, Bossers K, Janky R, Salta E, Frigerio CS, Barbash S, et al. Alteration of the microRNA network during the progression of Alzheimer's disease. EMBO Mol Med. 2013;5:1613–34.
• [150]Smith PY, Delay C, Girard J, Papon MA, Planel E, Sergeant N, et al. MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy. Hum Mol Genet. 2011;20:4016–24.
• [151]Duff K, Knight H, Refolo LM, Sanders S, Yu X, Picciano M, Malester B, Hutton M, Adamson J, Goedert M et al.. Characterization of pathology in transgenic mice over-expressing human genomic and cDNA tau transgenes. Neurobiol Dis. 2000; 7:87-98.
• [152]Hanes J, Zilka N, Bartkova M, Caletkova M, Dobrota D, Novak M. Rat tau proteome consists of six tau isoforms: implication for animal models of human tauopathies. J Neurochem. 2009; 108:1167-1176.
• [153]Janke C, Beck M, Stahl T, Holzer M, Brauer K, Bigl V, et al. Phylogenetic diversity of the expression of the microtubule-associated protein tau: implications for neurodegenerative disorders. Brain Res Mol Brain Res. 1999;68:119–28.
• [154]McMillan P, Korvatska E, Poorkaj P, Evstafjeva Z, Robinson L, Greenup L, et al. Tau isoform regulation is region- and cell-specific in mouse brain. J Comp Neurol. 2008;511:788–803.
• [155]Takuma H, Arawaka S, Mori H. Isoforms changes of tau protein during development in various species. Brain Res Dev Brain Res. 2003; 142:121-127.
• [156]Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS. Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem. 2013; 127:739-749.
• [157]Lee G, Cowan N, Kirschner M. The primary structure and heterogeneity of tau protein from mouse brain. Science. 1988; 239:285-288.
• [158]Cohen JE, Lee PR, Fields RD. Systematic identification of 3'-UTR regulatory elements in activity-dependent mRNA stability in hippocampal neurons. Philos Trans R Soc Lond B Biol Sci. 2014;369.
• [159]Aranda-Abreu GE, Behar L, Chung S, Furneaux H, Ginzburg I. Embryonic lethal abnormal vision-like RNA-binding proteins regulate neurite outgrowth and tau expression in PC12 cells. J Neurosci. 1999; 19:6907-6917.
• [160]Aronov S, Aranda G, Behar L, Ginzburg I. Axonal tau mRNA localization coincides with tau protein in living neuronal cells and depends on axonal targeting signal. J Neurosci. 2001; 21:6577-6587.
• [161]Aronov S, Marx R, Ginzburg I. Identification of 3'UTR region implicated in tau mRNA stabilization in neuronal cells. J Mol Neurosci. 1999; 12:131-145.
• [162]Larcher JC, Gasmi L, Viranaicken W, Edde B, Bernard R, Ginzburg I, et al. Ilf3 and NF90 associate with the axonal targeting element of Tau mRNA. FASEB J. 2004;18:1761–3.