The Tauopathies
1999; Elsevier BV; Volume: 154; Issue: 1 Linguagem: Inglês
10.1016/s0002-9440(10)65242-x
ISSN1525-2191
AutoresMichel Goedert, Masato Hasegawa,
Tópico(s)Prion Diseases and Protein Misfolding
ResumoAbundant intraneuronal neurofibrillary lesions within certain brain regions constitute a defining neuropathological characteristic of Alzheimer's disease.1Spillantini MG Goedert M Tau protein pathology in neurodegenerative diseases.Trends Neurosci. 1998; 21: 428-433Abstract Full Text Full Text PDF PubMed Scopus (619) Google Scholar Ultrastructurally, the neurofibrillary lesions consist of abnormal filamentous deposits in the form of paired helical filaments (PHFs) and the related straight filaments (SFs). These filaments are made of the microtubule-associated protein tau in a hyperphosphorylated state. In normal brain, tau protein is soluble and nonfilamentous. Its ordered assembly into filaments is therefore a pathological event. Tau pathology is not limited to Alzheimer's disease but is also present in a number of other dementing disorders, such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.2Dickson DW Pick's disease: a modern approach.Brain Pathol. 1998; 8: 839-854Google Scholar, 3Bergeron C Davis A Lang AE Corticobasal degeneration and progressive supranuclear palsy presenting with cognitive decline.Brain Pathol. 1998; 8: 355-365Crossref PubMed Scopus (101) Google Scholar In these disorders, as in Alzheimer's disease, the hyperphosphorylated tau protein is filamentous. However, the filament morphologies and tau isoform compositions differ from those of Alzheimer's disease. The good correlation between the presence of tau pathology and the degree of cognitive impairment has suggested that the events leading to the formation of tau filaments or the mere presence of these filaments are sufficient to produce nerve cell degeneration. Recently, this view has been significantly reinforced by the discovery of mutations in the tau gene in familial frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17).4Poorkaj 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; 43: 815-825Crossref PubMed Scopus (1253) Google Scholar, 5Hutton M Lendon CL Rizzu P Baker M Froelich S Houlden H Pickering-Brown S Chakraverty S Isaacs A Grover A Hackett J Adamson J Lincoln S Dickson D Davies P Petersen RC Stevens M de Graaff E Wauters E van Baren J Hillebrand M Joosse M Kwon JM Nowotny P Che LK Norton J Morris JC Reed LA Trojanowski JQ Basun H Lannfelt L Neystat M Fahn S Dark F Tannenberg T Dodd P Hayward N Kwok DBJ Schofield PR Andreadis A Snowden J Craufurd A Neary D Owen F Oostra BA Hardy J Goate A Van Swieten J Mann D Lynch T Heutink P Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.Nature. 1998; 393: 702-705Crossref PubMed Scopus (2985) Google Scholar, 6Spillantini MG Murrell JR Goedert M Farlow MR Klug A Ghetti B Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.Proc Natl Acad Sci USA. 1998; 95: 7737-7741Crossref PubMed Scopus (1340) Google Scholar, 7Dumanchin C Camuzat A Campion D Verpillat P Hannequin D Dubois B Saugier-Veber P Martin C Penet C Charbonnier F Agid Y Frebourg T Brice A Segregation of a missense mutation in the microtubule-associated protein tau with familial frontotemporal dementia and parkinsonism.Hum Mol Genet. 1998; 7: 1825-1829Crossref PubMed Scopus (220) Google Scholar, 8Clark LN Poorkaj P Wszolek Z Geschwind DH Nasreddine ZS Miller B Li D Payami H Awert F Markopoulou K Andreadis A D'Souza I Lee VMY Reed L Trojanowski JQ Zhukareva V Bird T Schellenberg G Wilhelmsen KC Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.Proc Natl Acad Sci USA. 1998; 95: 13103-13107Crossref PubMed Scopus (453) Google Scholar The new work will no doubt lead to increased efforts aimed at producing experimental animal models of the tau pathology of Alzheimer's disease and other tauopathies. Tau protein promotes microtubule assembly and binds to microtubules, which are thus stabilized. In adult human brain six tau isoforms are expressed; they are produced by alternative mRNA splicing from a single gene located on the long arm of chromosome 17 (Figure 1). They differ by the presence of three or four tandem repeats of 31 or 32 amino acids each located in the carboxyl-terminal region in conjunction with 0, 29, or 58 amino acid inserts located in the amino-terminal region.9Goedert 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 mRNAs in human brain.EMBO J. 1989; 8: 393-399Crossref PubMed Scopus (888) Google Scholar, 10Goedert 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: 519-526Abstract Full Text PDF PubMed Scopus (1976) Google Scholar There is also a larger tau isoform, with an additional insert in the amino-terminal region, which is mainly expressed in the peripheral nervous system.11Goedert M Spillantini MG Crowther RA Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system.Proc Natl Acad Sci USA. 1992; 89: 1983-1987Crossref PubMed Scopus (235) Google Scholar, 12Couchie D Mavilia C Georgieff IS Liem RKH Shelanski ML Nunez J Primary structure of high molecular weight tau present in the peripheral nervous system.Proc Natl Acad Sci USA. 1992; 89: 4378-4381Crossref PubMed Scopus (218) Google Scholar Eleven exons contribute to the longest human brain tau isoform, with exons 2, 3, and 10 being subject to alternative mRNA splicing.9Goedert 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 mRNAs in human brain.EMBO J. 1989; 8: 393-399Crossref PubMed Scopus (888) Google Scholar, 10Goedert 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: 519-526Abstract Full Text PDF PubMed Scopus (1976) Google Scholar, 13Andreadis A Brown MW Kosik KS Structure and novel exons of the human tau gene.Biochemistry. 1992; 31: 10626-10633Crossref PubMed Scopus (507) Google Scholar Tau expression is developmentally regulated in that only the tau isoform with three repeats and no amino-terminal inserts is present in fetal brain. There exist true species differences in the expression of tau isoforms in adult brain. Thus, only four-repeat tau isoforms are expressed in rodent brain. By contrast, all six tau isoforms are expressed in adult human brain, where tau isoforms with three repeats are slightly more abundant than tau isoforms with four repeats. The repeat regions of tau and sequences flanking the repeats constitute microtubule-binding domains.14Gustke N Trinczek B Biernat J Mandelkow EM Mandelkow E Domains of tau protein and interactions with microtubules.Biochemistry. 1994; 33: 9511-9522Crossref PubMed Scopus (549) Google Scholar, 15Goode BL Denis PE Panda D Radeke MJ Miller HP Wilson L Feinstein SC Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.Mol Biol Cell. 1997; 8: 353-365Crossref PubMed Scopus (243) Google Scholar Tau is expressed predominantly in nerve cells, with lower levels in some glial cells. Within nerve cells, it is found mainly in axons.16Binder LI Frankfurter A Rebhun LI The distribution of tau in the mammalian nervous system.J Cell Biol. 1985; 101: 1371-1378Crossref PubMed Scopus (1333) Google Scholar Inactivation of the tau gene by homologous recombination leads to no overt phenotype, indicating that tau is not an essential protein.17Harada A Oguchi K Okabe S Kuno J Terada S Oshima T Sato-Yoshitake R Takei Y Noda T Hirokawa N Altered microtubule organization in small-calibre axons of mice lacking tau protein.Nature. 1994; 369: 488-491Crossref PubMed Scopus (614) Google Scholar Tau is a phosphoprotein and phosphorylation is also developmentally regulated. Thus, tau from developing brain is phosphorylated more than tau from adult brain. Tau from the PHFs and SFs of Alzheimer's disease brain is hyperphosphorylated and abnormally phosphorylated on all six isoforms compared to tau from normal adult human brain.18Goedert M Spillantini MG Cairns NJ Crowther RA Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms.Neuron. 1992; 8: 159-168Abstract Full Text PDF PubMed Scopus (949) Google Scholar, 19Morishima-Kawashima M Hasegawa M Takio K Suzuki M Yoshida H Titani K Ihara Y Proline-directed and non-proline-directed phosphorylation of PHF-tau.J Biol Chem. 1995; 270: 823-829Crossref PubMed Scopus (536) Google Scholar This contrasts with progressive supranuclear palsy and corticobasal degeneration, where only four-repeat tau isoforms are found in the abnormal filaments.20Flament S Delacourte A Verny M Hauw JJ Javoy-Agid F Abnormal tau proteins in progressive supranuclear palsy: similarities and differences with the neurofibrillary degeneration of the Alzheimer type.Acta Neuropathol. 1991; 81: 591-596Crossref PubMed Scopus (199) Google Scholar, 21Delacourte A Buée L Normal and pathological tau proteins as factors for microtubule assembly.Int Rev Cytol. 1997; 171: 167-224Crossref PubMed Google Scholar, 22Ksiezak-Reding H Morgan K Mattiace LA Davies P Liu WK Yen SH Weidenheim K Dickson DW Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration.Am J Pathol. 1994; 145: 1496-1508PubMed Google Scholar In Pick's disease, the tau filaments consist only of three-repeat isoforms.23Sergeant N David JP Lefranc D Vermersch P Wattez A Delacourte A Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases.FEBS Lett. 1997; 412: 578-582Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Hyperphosphorylation and abnormal phosphorylation are major biochemical abnormalities of filamentous tau. They are early events in the development of tau filaments and as a result tau is unable to bind to microtubules.24Braak E Braak H Mandelkow EM A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads.Acta Neuropathol. 1994; 87: 554-562Crossref PubMed Scopus (676) Google Scholar, 25Bramblett GT Goedert M Jakes R Merrick SE Trojanowski JQ Lee VMY Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding.Neuron. 1993; 10: 1089-1099Abstract Full Text PDF PubMed Scopus (793) Google Scholar, 26Yoshida H Ihara Y Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament tau.J Neurochem. 1993; 61: 1183-1186Crossref PubMed Scopus (212) Google Scholar However, it is unclear whether hyperphosphorylation and abnormal phosphorylation are sufficient for the assembly of tau into filaments. Over the past few years, familial frontotemporal dementias, some with parkinsonism, have been recognized as FTDP-17, a previously unknown group of dementia disorders.27Foster NL Wilhelmsen K Sima AAF Jones MZ D'Amato C Gilman S Spillantini MG Lynch T Mayeux RP Gaskell PC Hulette C Pericak-Vance MA Welsh-Bohmer KA Dickson DW Heutink P Kros J Van Swieten JC Arwert F Ghetti B Murrell J Lannfelt L Hutton M Phelps CH Snyder DS Oliver E Ball MJ Cummings JL Miller BL Katzman R Reed L Schelper RL Lanska DJ Brun A Fink JK Khul DE Knopman DS Wszolek Z Miller CL Bird TD Lendon C Elechi C Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus statement.Ann Neurol. 1997; 41: 706-715Crossref PubMed Scopus (606) Google Scholar Their unifying pathological characteristic is the presence of abundant filamentous hyperphosphorylated tau deposits in the absence of Aβ amyloid plaques. In some of these families tau deposits are found in both nerve cells and glial cells, whereas in others only nerve cells are affected.28Spillantini MG Bird TD Ghetti B Frontotemporal dementia and parkinsonism linked to chromosome 17: a new group of tauopathies.Brain Pathol. 1998; 8: 387-402Crossref PubMed Scopus (390) Google Scholar Besides having a filamentous tau pathology in common, the familial frontotemporal dementias also share linkage to chromosome 17q21-22, the same region that contains the tau gene.29Wilhelmsen KC Lynch T Pavlou E Higgins M Nygaard TG Localization of disinhibition-dementia-Parkinsonism-amyotrophy complex to 17q21–22.Am J Hum Genet. 1994; 55: 1159-1165PubMed Google Scholar Recently, the first mutations in the tau gene have been identified in several of these families.4Poorkaj 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; 43: 815-825Crossref PubMed Scopus (1253) Google Scholar, 5Hutton M Lendon CL Rizzu P Baker M Froelich S Houlden H Pickering-Brown S Chakraverty S Isaacs A Grover A Hackett J Adamson J Lincoln S Dickson D Davies P Petersen RC Stevens M de Graaff E Wauters E van Baren J Hillebrand M Joosse M Kwon JM Nowotny P Che LK Norton J Morris JC Reed LA Trojanowski JQ Basun H Lannfelt L Neystat M Fahn S Dark F Tannenberg T Dodd P Hayward N Kwok DBJ Schofield PR Andreadis A Snowden J Craufurd A Neary D Owen F Oostra BA Hardy J Goate A Van Swieten J Mann D Lynch T Heutink P Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.Nature. 1998; 393: 702-705Crossref PubMed Scopus (2985) Google Scholar, 6Spillantini MG Murrell JR Goedert M Farlow MR Klug A Ghetti B Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.Proc Natl Acad Sci USA. 1998; 95: 7737-7741Crossref PubMed Scopus (1340) Google Scholar, 7Dumanchin C Camuzat A Campion D Verpillat P Hannequin D Dubois B Saugier-Veber P Martin C Penet C Charbonnier F Agid Y Frebourg T Brice A Segregation of a missense mutation in the microtubule-associated protein tau with familial frontotemporal dementia and parkinsonism.Hum Mol Genet. 1998; 7: 1825-1829Crossref PubMed Scopus (220) Google Scholar, 8Clark LN Poorkaj P Wszolek Z Geschwind DH Nasreddine ZS Miller B Li D Payami H Awert F Markopoulou K Andreadis A D'Souza I Lee VMY Reed L Trojanowski JQ Zhukareva V Bird T Schellenberg G Wilhelmsen KC Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.Proc Natl Acad Sci USA. 1998; 95: 13103-13107Crossref PubMed Scopus (453) Google Scholar They are either missense mutations in the microtubule-binding repeat region and the carboxy-terminal region or intronic mutations that change the ratio of three-repeat to four-repeat tau isoforms. Missense mutations have been found in exons 9, 10, 12, and 13 of the tau gene; they change glycine residue 272 to valine (G272V), asparagine residue 279 to lysine (N279K), proline residue 301 to leucine (P301L), valine residue 337 to methionine (V337M), and arginine residue 406 to tryptophan (R406W) (numbering accords with the 441-amino acid isoform of human tau). The N279K and P301L mutations lie in the extra repeat of tau, thus affecting only four-repeat tau isoforms. By contrast, the other three missense mutations are found in all six brain tau isoforms. Four different intronic mutations are found in the region of the exon 10 splice-donor site, where they disrupt a predicted stem-loop. This disruption leads to increased splicing of exon 10, resulting in the overproduction of four-repeat tau isoforms and reduced levels of tau isoforms with three repeats.5Hutton M Lendon CL Rizzu P Baker M Froelich S Houlden H Pickering-Brown S Chakraverty S Isaacs A Grover A Hackett J Adamson J Lincoln S Dickson D Davies P Petersen RC Stevens M de Graaff E Wauters E van Baren J Hillebrand M Joosse M Kwon JM Nowotny P Che LK Norton J Morris JC Reed LA Trojanowski JQ Basun H Lannfelt L Neystat M Fahn S Dark F Tannenberg T Dodd P Hayward N Kwok DBJ Schofield PR Andreadis A Snowden J Craufurd A Neary D Owen F Oostra BA Hardy J Goate A Van Swieten J Mann D Lynch T Heutink P Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17.Nature. 1998; 393: 702-705Crossref PubMed Scopus (2985) Google Scholar, 6Spillantini MG Murrell JR Goedert M Farlow MR Klug A Ghetti B Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.Proc Natl Acad Sci USA. 1998; 95: 7737-7741Crossref PubMed Scopus (1340) Google Scholar The functional consequences of missense mutations in tau have been studied in microtubule assembly experiments.30Hasegawa M Smith MJ Goedert M Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly.FEBS Lett. 1998; 437: 207-210Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar All the mutations investigated showed a markedly reduced ability to promote microtubule assembly. The P301L mutation produced the largest effect, the R406W mutation the smallest effect, and the G272V and V337M mutations intermediate reductions. This partial loss of function may be the primary effect of these missense mutations in tau. It may be followed by the hyperphosphorylation of tau and, through interaction with other cellular factors, by assembly into filaments. Similarly, overproduction of four-repeat tau isoforms in cases with intronic mutations may result in the inability of some of the excess tau to bind to microtubules, leading to its hyperphosphorylation and assembly into filaments. Most missense mutations are likely to lead to a reduced ability of tau to interact with microtubules. The N279K mutation may be an exception, since it creates an exon splice enhancer sequence, which may lead to increased splicing of exon 10.8Clark LN Poorkaj P Wszolek Z Geschwind DH Nasreddine ZS Miller B Li D Payami H Awert F Markopoulou K Andreadis A D'Souza I Lee VMY Reed L Trojanowski JQ Zhukareva V Bird T Schellenberg G Wilhelmsen KC Pathogenic implications of mutations in the tau gene in pallido-ponto-nigral degeneration and related neurodegenerative disorders linked to chromosome 17.Proc Natl Acad Sci USA. 1998; 95: 13103-13107Crossref PubMed Scopus (453) Google Scholar There may be mutations in tau that produce effects on both microtubule assembly and on mRNA splicing of exon 10. In Seattle family A (with the V337M mutation), in familial multiple-system tauopathy with presenile dementia (with the +3 mutation in the intron following exon 10), in the Iowa family (with the R406W mutation), in pallido-ponto-nigral degeneration (with the N279K mutation), and in Dutch family 1 (with the P301L mutation), tau is hyperphosphorylated at the same sites as in Alzheimer's disease.31Spillantini MG Crowther RA Goedert M Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles.Acta Neuropathol. 1996; 92: 42-48Crossref PubMed Scopus (149) Google Scholar, 32Spillantini MG Goedert M Crowther RA Murrell J Farlow MJ Ghetti B Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.Proc Natl Acad Sci USA. 1997; 94: 4113-4118Crossref PubMed Scopus (311) Google Scholar, 33Reed LA Grabowski TJ Schmidt ML Morris JC Goate A Solodkin A Van Hoesen GW Schelper RL Talbot CJ Wragg MA Trojanowski JQ Autosomal dominant dementia with widespread neurofibrillary tangles.Ann Neurol. 1997; 42: 564-572Crossref PubMed Scopus (164) Google Scholar, 34Reed LA Schmidt ML Wszolek ZK Balin BJ Soontornniyomkij V Lee VMY Trojanowski JQ Schelper RL The neuropathology of a chromosome 17-linked autosomal dominant Parkinsonism and dementia ("pallido-ponto-nigral degeneration").J Neuropathol Exp Neurol. 1998; 57: 588-601Crossref PubMed Scopus (141) Google Scholar, 35Spillantini MG Crowther RA Kamphorst W Heutink P Van Swieten JC Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau.Am J Pathol. 1998; 153: 1359-1363Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar Pick-like bodies have been described in Dutch family 2 (with the G272V mutation) that show tau staining characteristics similar to those of classical Pick bodies.35Spillantini MG Crowther RA Kamphorst W Heutink P Van Swieten JC Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau.Am J Pathol. 1998; 153: 1359-1363Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 36Probst A Tolnay M Langui D Goedert M Spillantini MG Pick's disease: hyperphosphorylated tau protein segregates to the somatoaxonal compartment.Acta Neuropathol. 1996; 92: 588-596Crossref PubMed Scopus (161) Google Scholar The balance between tau protein levels and available binding sites on microtubules appears to be critical for determining whether or not tau assembles into filaments. Thus, a reduced ability to interact with microtubules appears to be the shared primary abnormality in tau protein resulting from the different exonic and intronic mutations described thus far. A partial loss of function may be necessary for the assembly of tau into filaments. The locations of the tau mutations appear to determine the nature of the pathology. Mutations in exon 10 or in the intron following exon 10 lead to a filamentous neuronal and glial cell tau pathology.32Spillantini MG Goedert M Crowther RA Murrell J Farlow MJ Ghetti B Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.Proc Natl Acad Sci USA. 1997; 94: 4113-4118Crossref PubMed Scopus (311) Google Scholar, 34Reed LA Schmidt ML Wszolek ZK Balin BJ Soontornniyomkij V Lee VMY Trojanowski JQ Schelper RL The neuropathology of a chromosome 17-linked autosomal dominant Parkinsonism and dementia ("pallido-ponto-nigral degeneration").J Neuropathol Exp Neurol. 1998; 57: 588-601Crossref PubMed Scopus (141) Google Scholar, 35Spillantini MG Crowther RA Kamphorst W Heutink P Van Swieten JC Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau.Am J Pathol. 1998; 153: 1359-1363Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar For exon 10 mutations, the filaments are narrow twisted ribbons consisting predominantly of tau isoforms with four microtubule-binding repeats.35Spillantini MG Crowther RA Kamphorst W Heutink P Van Swieten JC Tau pathology in two Dutch families with mutations in the microtubule-binding region of tau.Am J Pathol. 1998; 153: 1359-1363Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar In the case of the intronic mutations, the filaments are wide twisted ribbons consisting exclusively of four-repeat tau isoforms.32Spillantini MG Goedert M Crowther RA Murrell J Farlow MJ Ghetti B Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments.Proc Natl Acad Sci USA. 1997; 94: 4113-4118Crossref PubMed Scopus (311) Google Scholar This is reminiscent of progressive supranuclear palsy and corticobasal degeneration, suggesting that these largely sporadic diseases may also result from abnormalities in the splicing of exon 10 of the tau gene. Missense mutations located outside exon 10 lead to a predominantly neuronal pathology.31Spillantini MG Crowther RA Goedert M Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles.Acta Neuropathol. 1996; 92: 42-48Crossref PubMed Scopus (149) Google Scholar, 33Reed LA Grabowski TJ Schmidt ML Morris JC Goate A Solodkin A Van Hoesen GW Schelper RL Talbot CJ Wragg MA Trojanowski JQ Autosomal dominant dementia with widespread neurofibrillary tangles.Ann Neurol. 1997; 42: 564-572Crossref PubMed Scopus (164) Google Scholar The tau filaments are PHFs and SFs and consist of all six tau isoforms. In the case of the V337M mutation in exon 12, the tau filaments have been shown to be indistinguishable from those of Alzheimer's disease.31Spillantini MG Crowther RA Goedert M Comparison of the neurofibrillary pathology in Alzheimer's disease and familial presenile dementia with tangles.Acta Neuropathol. 1996; 92: 42-48Crossref PubMed Scopus (149) Google Scholar Phosphorylated full-length recombinant tau has consistently failed to assemble into PHF-like filaments in in vitro experiments. By contrast, incubation of recombinant tau with sulphated glycosaminoglycans, such as heparin and heparan sulphate, results in the bulk assembly of tau into Alzheimer-like filaments.37Goedert M Jakes R Spillantini MG Hasegawa M Smith MJ Crowther RA Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans.Nature. 1996; 383: 550-553Crossref PubMed Scopus (888) Google Scholar, 38Pérez M Valpuesta JM Medina M Montejo de Garcini E Avila J Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction.J Neurochem. 1996; 67: 1183-1190Crossref PubMed Scopus (381) Google Scholar, 39Arrasate M Pérez M Valpuesta JM Avila J Role of glycosaminoglycans in determining the helicity of paired helical filaments.Am J Pathol. 1997; 151: 1115-1122PubMed Google Scholar, 40Hasegawa M Crowther RA Jakes R Goedert M Alzheimer-like changes in microtubule-associated protein tau induced by sulfated glycosaminoglycans. Inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation.J Biol Chem. 1997; 272: 33118-33124Crossref PubMed Scopus (194) Google Scholar, 41Qi Z Zhu X Goedert M Fujita DJ Wang JH Effect of heparin on phosphorylation site specificity of neuronal Cdc2-like kinase.FEBS Lett. 1998; 423: 227-230Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 42Friedhoff P Schneider A Mandelkow EM Mandelkow E Rapid assembly of Alzheimer-like paired helical filaments from microtubule-associated protein tau monitored by fluorescence in solution.Biochemistry. 1998; 37: 10223-10230Crossref PubMed Scopus (365) Google Scholar Tau isoforms with three repeats assemble into twisted paired helical-like filaments, whereas tau isoforms with four repeats assemble into straight filaments.37Goedert M Jakes R Spillantini MG Hasegawa M Smith MJ Crowther RA Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans.Nature. 1996; 383: 550-553Crossref PubMed Scopus (888) Google Scholar Immunoelectron microscopy shows that the paired helical-like filaments are decorated by antibodies directed against the amino- and carboxy-termini of tau, but not by an antibody directed against the microtubule-binding repeat region.37Goedert M Jakes R Spillantini MG Hasegawa M Smith MJ Crowther RA Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans.Nature. 1996; 383: 550-553Crossref PubMed Scopus (888) Google Scholar These results, which indicate that in the filaments the repeat region of tau is inaccessible to the antibody, are identical to those previously obtained with PHFs from the brains of Alzheimer's disease patients.18Goedert M Spillantini MG Cairns NJ Crowther RA Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms.Neuron. 1992; 8: 159-168Abstract Full Text PDF PubMed Scopus (949) Google Scholar They establish that the microtubule-binding repeat region of tau is essential for sulphated glycosaminoglycan-induced filament formation. Three microtubule-binding repeats of tau are also believed to form the core of the PHFs found in the brains of Alzheimer's disease patients, supporting the evidence for a similar organization of the two types of filament. Previous experiments had shown that three recombinant microtubule-binding repeats of tau assemble into twisted filaments in vitro.43Wille H Drewes G Biernat J Mandelkow EM Mandelkow E Alzheimer-like paired helical filaments and antiparallel dimers formed from microtubule-associated protein tau in vitro.J Cell Biol. 1992; 118: 573-584Crossref PubMed Scopus (443) Google Scholar, 44Crowther RA Olesen OF Jakes R Goedert M The microtubule-binding repeats of tau protein assemble into filaments like those found in Alzheimer's disease.FEBS Lett. 1992; 309: 199-202Abstract Full Text PDF PubMed Scopus (147) Google Scholar This assembly is phosphorylation-independent and occurs in the absence of sulphated glycosaminoglycans. It confirms that three repeats are required to give the morphology of the PHF. However, these experiments do not shed light on the mechanisms that lead to tau filament formation in the brains of Alzheimer's disease patients, because PHF-tau is made of full-length tau. The dimensions of tau filaments formed in the presence of sulphated glycosaminoglycans are similar to those of filaments extracted from brains of Alzheimer's disease patients, with diameters of approximately 20 nm for twisted and 15 nm for straight filaments and a crossing-over spacing of approximately 80 nm for paired helical-like filaments, although their twist is in general less regular than that found in Alzheimer's disease filaments. Sulphated glycosaminoglycans also stimulate phosphorylation of tau by a number of protein kinases, prevent the binding of tau to taxol-stabilized microtubules, and disassemble microtubules assembled from tau and tubulin.37Goedert M Jakes R Spillantini MG Hasegawa M Smith
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