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Human Molecular Genetics 2006 15(Review Issue 2):R188-R195; doi:10.1093/hmg/ddl190
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Untangling the tau gene association with neurodegenerative disorders

Alan M. Pittman1, Hon-Chung Fung1,2,3 and Rohan de Silva1,*

1 Reta Lila Weston Institute of Neurological Studies, University College London, 1, Wakefield Street, London WC1N 1PJ, UK, 2 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Porter Neuroscience Building, 35 Convent Drive, Bethesda, MD 20892, USA and 3 Department of Neurology, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taipei, Taiwan

* To whom correspondence should be addressed. Tel: +44 2076794264; Fax: +44 2076794236; Email: rsilva{at}ion.ucl.ac.uk

Received July 5, 2006; Accepted July 25, 2006


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 
Pathological tau protein inclusions have long been recognized to define the diverse range of neurodegenerative disorders called the tauopathies, which include Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration. Mutations in the tau gene, MAPT, cause familial frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and common variation in MAPT is strongly associated with the risk of PSP, corticobasal degeneration and, to a lesser extent, AD and Parkinson's disease (PD), implicating the involvement of tau in common neurodegenerative pathway(s). This review will discuss recent work towards the unravelling of the functional basis of this MAPT gene association. The region of chromosome 17q21 containing MAPT locus is characterized by the complex genomic architecture, including a large inversion that leads to a bipartite haplotype architecture, an inversion-mediated deletion and multiplications resulting from non-allelic homologous recombination between the MAPT family of low-copy repeats.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 
The microtubule (MT)-associated protein, tau, was first identified as a ‘factor essential for MT assembly’, a heat stable protein that induced the assembly of MTs from purified tubulin and belonging to the family of MT-associated proteins (1). Tau is abundantly expressed in both the peripheral and central nervous system (2), where it is enriched in the axons of mature and growing neurones. Low levels of tau are also present in oligodendrocytes and astrocytes (3,4). Tau is a phosphoprotein with developmentally regulated phosphorylation profiles at up to 38 phosphorylation sites (reviewed in 5). The level of protein phosphorylation is highly elevated in fetal tau and pathological tau found within the insoluble, fibrillar inclusions that define tauopathies, compared with normal adult brain tau (6).

The human tau gene, MAPT (MIM 157140 [OMIM] ), spanning ~150 kb of nucleotide sequence on chromosome 17q21.3, consists of one non-coding- and 14 coding exons (7–9) (Fig. 1). In the healthy adult human brain, tau protein exists as six major isoforms produced by the alternative splicing of exons 2, 3 and 10 (10) (Fig. 1). The alternative splicing of exon 10 produces tau isoforms with either three MT-binding repeats (3R-tau) due to exclusion of exon 10 or four repeats (4R-tau) due to exon 10 inclusion. It is now widely recognized that several tauopathies are associated with aberrant splicing of exon 10, causing imbalances in the 3R-tau:4R-tau ratios. For example, the insoluble tau deposits in the different tauopathies have different tau-isoform compositions; in Pick's disease (PiD), the classical Pick bodies consist mainly of 3R-tau isoforms (11,12), whereas in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and argyrophilic grain disease, both neuronal and glial inclusions contain mostly 4R-tau isoforms (13–16), and roughly equal amounts of 3R- and 4R-tau make up the paired helical filaments and straight filaments observed in Alzheimer' disease (AD) (16,17).


Figure 1901
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  		Figure 1. (Top) Tau in the central nervous system (CNS) exists as six isoforms due to the alternative splicing of exons 2, 3 and 10 (yellow boxes). Exons 4A, 7 and 8 (red boxes) are absent in the CNS and exon 4A is included in peripheral nervous system tau. Exons 2 and 3 code for N-terminal inserts, alternative splicing leads to tau isoforms with 2, 1 or no N-terminal inserts (2N, 1N or 0N). Exon 10 codes for one of four MT binding domains—alternative splicing results in tau with three or four MT binding repeat domains (3R, 4R). FTDP-17 missense and silent mutations and deletions are indicated with numbering relating to the longest 441 residue 2N,4R isoform. Mutations in red affect the alternative splicing of exon 10. Proportions are not to scale. (Bottom) FTDP-17 mutations affecting the splicing of exon 10. The majority of these mutations disrupt a predicted pre-mRNA stem-loop structure, inducing increased incorporation of exon 10. Partial sequence of exon 10 in red. Intronic sequence in black. Proportions are not to scale. Modified from Goedert (21).

 

   CHROMOSOME 17q21: A FRONTOTEMPORAL DEMENTIA HOTSPOT
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 
After the first identification of mutations in the tau gene (MAPT) in FTDP-17 (18,19), over 35 mutations in more than 100 families to date have established the importance of tau dysfunction as central in the aetiopathogenesis of these disorders. The mutations affecting MAPT in FTDP-17 can be divided into two classes, the missense and the exon 10 splicing mutations (Fig. 1) (recently reviewed in 20–22). The chief effect of the former is in the biochemistry of the tau protein, where in most cases, the MT-binding capacity is reduced, leading to a greater abundance of unbound tau species that could lead to aggregation and the formation of the insoluble tau inclusions that characterize these disorders. The exon 10 splicing mutations in the main cause increased incorporation of exon 10, thereby increasing the relative levels of 4R-tau isoforms. Although classified under the rubric of FTDP-17, these disorders have diverse clinical phenotypes including movement disorders such as PSP and CBD, memory dysfunction similar to that found in AD and typical clinical pictures observed in PiD/frontotemporal lobar degeneration (23). In fact, there are reports of the same mutation, P301L causing either CBD or FTDP in the same family (24). It is therefore clear that the manifestations of each mutation are subject to potential epigenetic and perhaps environmental influences and the question of genotype–phenotype correlation is complex (25,26).

In addition to FTDP-17, another group of familial frontotemporal dementias (FTDs) with intranuclear ubiquitin inclusions, but lacking any tau pathology, was linked to the same region of chromosome 17q21 (FTDU-17) (27–29). This region is defined by the markers D17S1787–D17S806 and contains MAPT (27). Extensive sequencing of MAPT failed to reveal any mutations (30), which presented the possibility of genomic rearrangements affecting MAPT. However, two groups have now shown that FTDU-17 is caused by at least 13 different null-mutations in the progranulin (GRN) gene, just 1.5 Mb away from MAPT (31,32). Identification of mutations not only in the FTDU-17 cases but also in a Belgian FTD patient series also showed that GRN mutations are 3.5 times more frequent cause of FTD when compared with MAPT (32).

Progranulin is a multifunctional growth factor, expressed in many tissues, including the brain, in both neurons and glia, and has been shown to be involved in several physiological and pathological processes, including wound repair, inflammation and activation of other growth factors such as vascular endothelial growth factor. Over-expression of GRN is associated with tumorigenesis (31,32).

Interestingly, most of the mutations identified cause haploinsufficiency and reduced levels of progranulin by creating null alleles (31,32). Nonsense, frameshift and splice-site mutations cause premature termination and degradation of the mutant mRNA by nonsense-mediated mRNA decay (31)—the mRNA from mutation carriers consisted almost entirely of the wild-type mRNA and very little mutant mRNA (31). Two mutations in the first methionine codon destroy the Kozak sequence (31,32).

The comparison of cellular pathways involved in tau and progranulin-related neurodegeneration will provide us with useful insights into the pathogenesis of the clinically similar FTDs and whether both would affect the same pathogenic pathways but different pathological outcomes.


   ASSOCIATION OF MAPT WITH SPORADIC TAUOPATHIES
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 
Conrad et al. (33) first reported a genetic predisposition to sporadic PSP involving MAPT. A single allele (a0) and its genotype (a0/a0) of a TG dinucleotide repeat marker located within intron 9 of the gene was significantly over-represented in PSP cases, compared with normal controls (33). A similar association was shown in the rarer tauopathy, CBD (34,35). The finding has now been confirmed in several independent studies (36–39), and Baker et al. (40) extended the association with PSP to the H1 haplotype, defined by a region of complete linkage disequilibrium (LD) spanning the entire coding sequence of MAPT. The H1 haplotype and its allelic counterpart, H2, were defined by a series of single nucleotide polymorphisms (SNPs), and a 238 bp deletion in intron 9 (del-In9) found only on the H2 background (40). The latter is now routinely used to unambiguously assign H1 and H2 haplotypes in MAPT genetic association studies (40). In Caucasian populations, the frequency of H1 varies between 70 and 80%; in PSP cases, this frequency is usually over 90% (Table 1). More controversially, the MAPT H1 haplotype and H1/H1 genotype have been shown to be associated with sporadic Parkinson's disease (PD) (41). However, this association has not been consistently replicated, although meta-analysis of all studies suggests that homozygosity of H1 contributes to increased risk of PD (41). These findings are surprising, as PD is not traditionally associated with the tau pathology.


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  		Table 1. Association studies of the MAPT locus and identified risk alleles in PSP

 
The association of the MAPT H1 haplotype, in the absence of coding mutations, suggests that underlying variation within the H1 haplotype clade plays a role in what possibly are common pathogenic pathways contributing to the complex aetiologies of these disorders. The most obvious effects could be on MAPT transcription, splicing or transcript stability—the 4R-tau dominant pathology seen in PSP and CBD brains would suggest aberrations in exon 10 alternative splicing.

The full extent of the LD and association of H1/H2 with PSP were mapped to cover a region of ~1.8 million base-pairs (42) and can now be confirmed by the analysis of genotype data for 17q21 from HapMap (http://www.hapmap.org). Indeed, it is the longest region of LD identified to date (43) and includes MAPT in the centre of this region, with other genes, including corticotrophin-releasing hormone receptor 1 (CRHR1), N-ethylmaleimide sensitive factor (NSF), IMP5 (44) and predicted genes of unknown function. This raises the possibility that a gene other than MAPT could be the actual culprit. For example, a novel gene, STH, coding for saitohin, is nested within intron 9 of MAPT. A Q7R polymorphism, which is in perfect LD with the H1 and H2 haplotypes, was shown to be associated with AD (45). However, like the H1 and H2 haplotypes, independent studies have failed to confirm this, and unsurprisingly, the Q variant and QQ genotype are over-represented in PSP (46,47). Further study of this gene and its protein would be required to ascertain its function and any disease-related effects.


   THE GENOMIC ARCHITECTURE OF THE MAPT LOCUS AT 17q21.3
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 
The extended region of complete LD due to the two non-recombining haplotype clades is due to an ancient inversion of a region of ~900 kb that includes MAPT (48–50). Detailed analysis of this region revealed multiple low-copy repeats (LCRs), which are the basis of the inversion and genomic complexity of this region by forming the substrates for non-allelic homologous recombination (Fig. 2) (30,49,50). The genomic complexity around the MAPT locus, mediated by the multiple LCRs, is underlined not only by complex arrangements of duplications close to the NSF gene (50) but also in a recently identified de novo microdeletion of 500–600 kb of the locus in individuals with developmental delay and learning disabilities (51,52). It is as yet unclear whether the developmental deficits in these cases were due to haploinsufficiency of the MAPT locus or the other affected genes, which include CRHR1 and IMP5 (44).


Figure 1902
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  		Figure 2. Inverted MAPT haplotypes at 17q21.31. H2 assembly is that of Stefansson et al. (50). H1D2 assembly is based on the human genome assembly of May 2004 (http://genome.ucsc.edu) and is for reference only, as H1 haplotypes show considerable structural diversity/copy number polymorphisms in the region of the 3' LCR B. Also shown are selected markers (30), the extended region of r2 LD (42), the MAPT microdeletion and genes (51,81); MT associated protein tau (MAPT), CRHR1 and NSF. The differences between the H1 and H2 assemblies are far from that of a simple inversion; other structural differences include segmental duplications and segmental duplications in inverted orientation.

 
Of particular interest is that the H2 haplotype is limited to the Europeans and other population groups with historical admixture with the Europeans. H2 is completely absent or very rare, in other African, Asian or native American populations (53). Genetic analysis of the H1 clade shows it to be variable and to have a normal pattern of LD (54,55). In contrast, the H2 haplotype is almost invariant, suggesting that it derives from a single founder. Analysis of the sequences on the H1 and H2 backgrounds and comparison of these sequences with those of the chimpanzee (Pan troglodytes) sequence show that although both H1 and H2 sequences are more similar to each other than the chimpanzee sequence, they do not follow a predictable relationship; at some sequences, the chimpanzee sequence is similar to H1, and at others, it is similar to H2 (56). Thus, the H1 and H2 sequences do not follow a precursor–product relationship and one cannot be derived from the other, rather both must have been derived independently from a more distant precursor predating the inversion (30,49). Although the estimated divergence of the H1 and H2 clades is ~3 million years ago, it is estimated that the H2 haplotype was re-introduced into the European population only about 10 000–30 000 years ago, overlapping with a period when Homo sapiens and Homo neanderthalensis co-existed in Europe. We have therefore suggested that the invariant H2 haplotype could have been derived from the neanderthals (49) with subsequent positive selection as shown in the Icelandic population (50). However, it is also possible that H2 represents a rare and early chromosomal change in Africa that rapidly expanded in European populations from a few founder chromosomes (50).


   MAPT HAPLOTYPE DIVERSITY AND DISEASE
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 
Although by definition all genes within the region of LD encompassing the MAPT locus are also associated with PSP, the hallmark tau pathology of this disorder strongly implicates MAPT itself. Several recent studies have analysed the population-wide haplotypic diversity of MAPT for case–control comparisons (30,54,55). This is with the ultimate goal of identifying the underlying mechanistic basis of the genetic association.

We utilized validated high-density genotype data from the International HapMap Project, which provides the useful basis for analysing this diversity in a representative Caucasian population (CEPH-Utah collection). A single H2 haplotype and multiple H1 variant haplotypes were identified (54). Using a minimal number of haplotype-tagging SNPs and the bi-allelic del-In9 marker for H1/H2 assignment (40,54), we determined that only one of the common (frequency >0.1) sub-haplotypes in the H1 clade, namely, H1c to be highly associated with PSP both in UK and US case–control cohorts. The H2 haplotype has a strong negative association with PSP, suggesting a protective function (40,54). Using a different approach, Rademakers et al. (55) also identified the association of a single common H1 sub-haplotype with PSP.

Although previous studies assessing the H1/H2 division in AD have been at best inconclusive (57–60), we have now shown that the H1c haplotype is also associated with sporadic AD (61), a result that we have now replicated in a separate pathologically confirmed case–control population study (Dr Amanda Myers, personal communication). This supports the notion that underlying variation within the H1c haplotype influences MAPT gene at the level of transcription, transcript stability and/or alternative splicing of exon 10. This influence could either be due to allele-specific differences caused by one or more SNPs or larger scale genomic polymorphisms involving MAPT. Likewise, some studies have shown an intriguing association of the H1 haplotype with PD, but many have failed to replicate this (38,62–66), although a meta-analysis of all these studies suggests a marginally increased risk (41). In a recent fine-mapping study of the H1 haplotpye in PD, Rademakers et al. (67) reported that in the absence of association of the extended H1 clade, sub-haplotype mapping revealed significant associations of a region around exon 10 in early-onset PD (age of onset <55 years) and a region upstream of exon 1 in late-onset PD. A 90 kb interval of the 5' end of MAPT was implicated in a study of the Norwegian PD cases (68).

These findings in AD and PD have also underlined the importance of more detailed analysis of the LD and haplotype pattern of an entire candidate locus using stringently matched case–control cohorts in order to confidently assess any potential association with disease. Consideration of the MAPT H1/H2 clade definition alone failed to establish a conclusive association, as they did not take into account the considerable inter-H1 variability.


   THE FUNCTIONAL BASIS OF THE MAPT ASSOCIATION
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
CONCLUSION
 REFERENCES
 
The identification of the H1c haplotype of MAPT as a modulator of risk of PSP, CBD, AD and PD provided the basis of a more targeted approach in dissecting the functional basis of the MAPT H1 association. Sequence polymorphisms within the H1c sub-haplotype could affect gene function, for example, by affecting one or more of the several (>100) evolutionarily conserved, potential cis-acting regulatory regions in the 5'- and 3'-untranslated regions of MAPT (69). On the basis of the most highly associated H1-specific tagging SNPs on the H1c background (rs242557, rs3785883 and rs2471738), we earmarked a minimal candidate region from the large intron upstream of MAPT exon 1 to the 3' region of intron 9 (54), encompassing potential regulation of both MAPT transcription and alternative splicing. Indeed, we have now shown that both transcription and splicing are affected; real-time allele-specific PCR quantitation in postmortem brain reveals that both total and exon 10-containing MAPT mRNA transcript levels are significantly higher in H1c when compared with the other H1 and H2 haplotypes (70). A possible basis for the increased expression is the H1-specific SNP, rs242557, which is located within intron 0 of the gene in an evolutionarily conserved island (>75% conservation between mouse and human), about 47 kb downstream from the MAPT core promoter at exon –1. Cellular reporter assays showed that this conserved domain is a putative control element for the MAPT core promoter and that the allelic variants of rs242557 alter this capacity (55). Cellular assays for transcriptional activity now show that the rs242557 allele A (as found in haplotype H1c) in conjunction with both the H1p and H2p variants of the MAPT core promoter (exon –1) (71,72) has significantly higher (2–4-fold, respectively) expression than the allele G (73).


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
REFERENCES
 
The MAPT gene is an interesting paradigm in the study of the genetic causes of human disease. Like amyloid pathology in AD and the subsequent identification of its originating protein and gene and mutations that cause the autosomal dominant familial forms of AD (74), tau pathology consisting of insoluble, fibrillar aggregates of tau has for long been the pathological hallmark of the tauopathies. The recent identification of MAPT mutations established the central importance of tau dysfunction in the aetiology of these disorders. However, like in AD and PD, the large majority of the cases are sporadic, caused by a combination of genetic and environmental risk factors and ageing. A common theme in many of the neurodegenerative disorders is the abnormal deposition of insoluble proteins, coded by the very genes that are mutated in a small number of the familial cases of these disorders. In the absence of protein defects caused by mutations, there are several other mechanisms that could lead to accumulation, misfolding and/or mislocalization of these proteins and the production of toxic aggregation intermediates. These could include oxidative damage, abnormal post-translational modifications (hyperphosphorylation, glycosylation, sumoylation, etc.) and defective ubiquitin–proteasome degradation. However, recent findings also implicate changes in expression levels of normal proteins caused by common genetic variability (75). For example, genetic variation in {alpha}-synuclein associated with PD modulates the disease risk by influencing protein expression (76). The over-production of protein as a result of gene multiplications such as {alpha}-synuclein in PD (77–79) and APP in AD (80) causes the disease. The MAPT haplotype association with sporadic tauopathies provides another clear example of a gene identified as a Mendelian pathogenic locus (in familial FTDP-17), contributing to risk for sporadic tauopathies by influencing either the expression of the protein or alternative splicing (75). This would be a potentially important therapeutic target for developing strategies to selectively reduce expression levels of pathogenic proteins.


   ACKNOWLEDGEMENTS
 
This work was supported by the Reta Lila Weston Trust for Medical Research (A.M.P. and R.d.S.) and the PSP (Europe) Association and Society for PSP, grants from the Bogue Fellowship of UCL and the Chang Gung Memorial Hospital Biomedical Scholarship to H.C.F. R.d.S. is funded by a research grant from the Medical Research Council (MRC), UK.

Conflict of Interest statement. None of the authors have declared any conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 CHROMOSOME 17q21: A...
 ASSOCIATION OF MAPT WITH...
 THE GENOMIC ARCHITECTURE OF...
 MAPT HAPLOTYPE DIVERSITY AND...
 THE FUNCTIONAL BASIS OF...
 CONCLUSION
 REFERENCES
 

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