The Biology and Pathology of Tau and its Role in Tauopathies II
The role of MAPT sequence variation in
mechanisms of disease susceptibility
Tara M. Caffrey* and Richard Wade-Martins*†1
*Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, U.K., and †Oxford Parkinson’s Disease Centre,
University of Oxford, South Parks Road, Oxford, OX1 3QX
Abstract
The microtubule-associated protein tau (MAPT or tau) is of great interest in the field of neurodegeneration
as there is a well-established genetic link between the MAPT gene locus and tauopathies, a diverse
group of neurodegenerative dementias and movement disorders. The genomic architecture in the region
spanning the MAPT locus contains a ∼1.8 Mb block of linkage disequilibrium characterized by two major
haplotypes: H1 and H2. Recent studies have established strong genetic association between the MAPT locus
and neurodegenerative disease and uncovered haplotype-specific differences in expression and alternative
splicing of MAPT transcripts. Integrating genetic association data and gene expression data to understand
how non-coding genetic variation at a gene locus affects gene expression and leads to susceptibility to
disease is a high priority in disease genetics, and the MAPT locus provides an excellent paradigm for
this. In the absence of protein-coding changes caused by haplotype sequence variation, altered levels of
protein expression or altered ratios of isoform expression are excellent candidate mechanisms to link the
MAPT genetic disease association with biological function. The use of novel transgenic and endogenous
genetic models are required to understand the role of MAPT sequence variation in mechanisms of disease
susceptibility.
Introduction
Intracellular aggregations of abnormally hyperphosphorylated microtubule-associated protein tau (MAPT or
tau), known as NFTs (neurofibrillary tangles), are the
major pathological feature of tauopathies, a diverse group
of neurodegenerative dementias and movement disorders
which includes AD (Alzheimer’s disease), PSP (progressive supranuclear palsy), CBD (corticobasal degeneration),
frontotemporal dementia and argyrophilic grain disease.
Identification of tau protein as the major component in
NFTs positions the MAPT locus as a leading causal candidate
gene in these neurodegenerative diseases [1,2]. Tau is a major
neuronal microtubule-associated protein expressed predominantly in the neurons of the central and peripheral nervous
systems [3,4]. Tau protein isoforms are expressed from the
MAPT locus located on chromosome 17q21 which consists
of 16 exons spanning 134 kb (http://genome.ucsc.edu/) [5]
(Figure 1). MAPT transcripts are temporally and spatially
regulated by alternative splicing. The alternative splicing of
exons 2, 3 and 10 generates six protein isoforms in the human
adult central nervous system, producing proteins ranging
from 352 to 441 amino acids in size [6,7]. The inclusion or
exclusion of exons 2 and 3 generates tau protein with zero,
Key words: MAPT, neurodegeneration, tau, tauopathy.
Abbreviations used: AD, Alzheimer’s disease; GWAS, genome-wide association study; iBAC,
infectious bacterial artificial chromosome; LOAD, late-onset AD; MAPT, microtubule-associated
protein tau; NFT, neurofibrillary tangle; OR, odds ratio; PAC, P1 artificial chromosome; PD,
Parkinson’s disease; PSP, progressive supranuclear palsy; SNP, single nucleotide polymorphism.
1
To whom correspondence should be addressed (email richard.wade-martins@dpag.
ox.ac.uk).
Biochem. Soc. Trans. (2012) 40, 687–692; doi:10.1042/BST20120063
one or two N-terminal inserts (0N, 1N, 2N tau). Transcripts
expressing exon 10 (exon 10 + ) generate proteins with four
microtubule-binding repeats (4R tau), whereas those lacking
exon 10 (exon 10 − ) generate three-repeat tau (3R tau).
Whereas the adult expresses six isoforms, human fetuses
express only the shortest tau isoform, lacking exons 2, 3 and 10
[8,9]. An additional protein isoform over 100 kDa is found in
the peripheral nervous system; this is generated by inclusion
of exon 4A in transcripts [10].
Genetic association
Investigation of polymorphisms within the MAPT gene led
to the elucidation of two extended haplotypes, H1 and
H2, covering the entire locus [11]. This block of linkage
disequilibrium spans a region covering approximately 1.8 Mb
[12] and is thought to exist as a result of the inversion of a
900 kb segment of the H2 chromosome with respect to its H1
counterpart [13]. Interestingly, although the H2 haplotype
remains largely invariant, exhaustive sequence analysis has
shown that recombination has continued within the H1 haplotype, generating a number of sub-haplotypes of H1 [12,14].
The common disease–common variant hypothesis proposes that commonly occurring alleles in the genome underlie
most common diseases [15]. The disease variants have been
sought by numerous genetic association studies which seek to
determine whether allele frequencies differ between patient
and control groups. The most recent high-powered GWASs
(genome-wide association studies) have yielded new insights
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Figure 1 Microtubule-associated protein tau
The human MAPT locus on chromosome 17q21 consists of 16 exons of which exons 2, 3 and 10 are alternatively spliced in
the adult central nervous system. Exons 4A and 8 (white) are absent from the CNS (central nervous system), but exon 4A is
expressed in the peripheral nervous system. Six tau isoforms are expressed in the adult CNS. Alternative splicing of exons 2
and 3 results in proteins with zero, one or two N-terminal inserts (0N, 1N, 2N). Splicing of exon 10 generates proteins with
either three or four microtubule-binding repeats (3R or 4R tau protein). The haplotypes demonstrate different patterns of
expression with the risk haplotype having greater total expression, greater expression of exon 10-containing transcripts and
lower expression of exon 3-containing transcripts.
into the risk associated with the common variants within the
H1 haplotype and neurodegenerative diseases.
Progressive supranuclear palsy
PSP is recognized as the second most common parkinsonian
neurodegenerative disorder, second only to idiopathic PD
(Parkinson’s disease) itself [16]. PSP is neuropathologically
characterized by neuronal globose neurofibrillary tangles and
neuropil threads and glial tau pathology including tufted
astrocytes [17]. The tau aggregates are formed predominately
of 4R tau, defining PSP as a 4R tauopathy.
The first genetic association between MAPT and neurodegenerative disease started with the identification of an
association between PSP and a polymorphic marker found
in MAPT intron 9 [18]. This genetic association was
subsequently expanded to include the entire MAPT H1
haplotype [11,18] and later refined to show the strongest
association with H1-specific haplotype tagging SNPs (single
nucleotide polymorphisms) (rs242557, rs3785883, rs2471738)
[12], suggesting it was variation within the H1 haplotype itself
that is the risk factor for developing PSP. The fine mapping
of these SNPs indicates that the association is conveyed by a
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upstream of exon 1 to 2.2 kb downstream of exon 9 [12].
In 2011, a GWAS was performed on 2165 PSP patients
and 6807 controls [19]. This study confirmed the highly
significant association of H1 polymorphisms with PSP with
extremely small P values (e.g. rs8070723, P = 1.5×10 − 116 ).
In the pathologically confirmed series of samples, this
association translated into a calculated OR (odds ratio)
of 5.5, which exceeds the well-established risk of APOE4
(apoplipoprotein E4) in AD (OR = 3.7) [20]. Further
examination of the risk alleles showed that after controlling
for the H1/H2 inversion, three SNPs continued to exhibit
a highly significant association, most notably rs242557 (P =
9.5×10 − 18 ) which was identified previously as an important
PSP-risk allele [12,14].
Alzheimer’s disease
AD is neuropathologically characterized by the presence of
both extracellular neuritic plaques formed of Aβ (amyloid βpeptide) and also intracellular NFTs. It is therefore perhaps
surprising that in the first large GWASs of AD cohorts,
there was no significant association of AD with MAPT
polymorphisms [21,22]. A subsequent meta-analysis of the
The Biology and Pathology of Tau and its Role in Tauopathies II
AD genetic association data by the team at AlzGene also has
not shown any association of MAPT with AD [20]. However,
a more recent analysis of LOAD (late-onset AD) consisting
of 3940 cases and 13 373 controls observed a significant
association of the MAPT locus (P = 0.009), although, notably,
no single marker reached genome-wide significance [23].
This analysis suggests that there exist multiple independent
associations across the MAPT gene with LOAD, although
each of which is likely to be of weak effect.
Parkinson’s disease
The most surprising GWAS findings were those that
identified MAPT variants among the most highly genetically
associated with PD, a neurodegenerative disease not
traditionally classified as a tauopathy [24–26]. Several
previous studies on much smaller cohorts had reported an
association of MAPT with PD [27,28], although this remained
controversial and had not always been replicated [29]. The
large GWASs and subsequent meta-analysis by the PDGene
forum (http://www.pdgene.org/) [30] now place MAPT as
the top-ranked gene for sporadic PD.
In the light of the highly significant genetic association
data, it is clear that understanding how non-coding genetic
variation at the MAPT locus affects gene expression and leads
to susceptibility to disease is a high priority in understanding
the molecular mechanisms of PSP and PD pathology. As the
MAPT risk alleles and haplotypes produce no protein coding
changes, the leading theories to explain the risk susceptibility
to disease focus on differences in expression and alternative
splicing.
Functional effects of genotype
Total MAPT expression
One leading theory to explain the neurodegenerative risk
susceptibility conferred by the H1 MAPT haplotype
proposes that DNA sequence variants drive expression
differences between the two haplotypes. Several studies have
attempted to study the effect of non-coding variation in the
promoter regulatory region of the MAPT locus on expression
of the gene.
Differences in the transcriptional activities of the MAPT
promoter haplotypes have been demonstrated by studies in
cell lines or using reporter gene assays. Early studies focusing
on the promoters gave some indication that the promoters
do indeed show different activities, as a 1 kb fragment of
the H2 promoter had a 1.2-fold reduction in transcriptional
activity compared with its H1 counterpart [31]. Other studies
have attempted to assess the effect of the PSP-risk associated
allele at rs242557. When this SNP was placed upstream of
a 1.1 kb fragment of the MAPT H1 promoter, the non-risk
allele showed greater transcriptional activity [14]. However,
in contrast, another study using this same SNP placed
downstream of the MAPT promoter region showed that the
H1 haplotype construct exhibits a 4.2-fold greater expression
than the H2 promoter [32]. Although both studies attempted
to narrow down the effect of this risk allele, their conflicting
results are probably because their experimental designs use
small fragments of regulatory sequence isolated from their
correct genomic context.
More physiologically relevant experiments have assayed
expression in human post-mortem brain tissue. Comparing
expression of the H1 and H2 haplotypes within heterozygous
pathology-free post-mortem human brain samples, no allelic
difference was observed in MAPT haplotype expression in
either the frontal cortex or globus pallidus [33], a finding
which has been replicated by another group [34]. The latter
study did, however, find that there was a relative decrease in
MAPT H1 expression with increased age [34]. Another study
used real-time PCR to assay allele-specific expression analysis
of MAPT and found a modest (11–13 %) greater expression
from chromosomes carrying a variant of H1: H1C [32].
Detailed analyses of expression have also been carried
out by the consortia which undertook GWASs. To assess
the possibility of polymorphisms affecting expression of the
MAPT transcripts haplotype, GWAS publications examined
correlation between gene expression and genotypes. In the
MAPT genomic region, the International Parkinson Disease
Genomic Consortium found that MAPT-risk SNPs were
associated with increased expression (P < 2×10 − 16 ) and
decreased methylation (P = 3.68×10 − 6 ) [26]. The consortium
which performed the PSP GWAS examined 387 normal
subjects and found significant association expression levels
with SNPs across the inversion region (MAPT, RL17A,
PLEKHM1 and LRRC27A4). This indicates that either
the orientation of this genomic region or a polymorphism
within it determines expression. Interestingly, although the
PSP GWAS showed significant association of both the H1
haplotype and variation within the H1, the global expression
of MAPT was unable to account for the risk conferred by
the rs242557 allele [19]. As the risk conferred by rs242557 is
unaccounted for, other modes of expression regulation should
also be considered.
MAPT alternative splicing
Another potential mechanism by which MAPT haplotypes
may confer susceptibility to neurodegeneration is through
the imbalanced expression of alternative transcripts. There
is much evidence to suggest that isoform imbalance may
play a role in tauopathies. An imbalance is observed in
familial dementia FTDP-17 in which MAPT exon 10 splice
site mutations act to increase the inclusion of exon 10 in
transcripts [35,36]. This gives evidence that an imbalance
in the ratio of 3R and 4R tau isoforms is sufficient to
cause disease. Further support for the role of imbalanced
tau isoforms in neurodegeneration comes from PSP in which
there is a significant increase in 4R MAPT mRNA transcript
in brain regions highly affected by neurodegeneration [37].
Expression studies focusing on the inclusion of exon 10
at the MAPT locus have identified differential expression
of alternatively spliced transcripts from the two MAPT
haplotypes. In post-mortem human brain tissues, the H1
MAPT variants overexpress the disease-associated exon 10
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compared with H2 [32,33]. In addition, the protective H2
haplotype has a 2-fold greater expression of transcripts
containing the alternatively spliced exons 2 and 3 [38]. In the
light of the allelic differences in expression of alternatively
spliced transcripts bearing exons 3 and 10, differences in tau
isoform expression may be an important factor in generating
susceptibility to sporadic tauopathies [39].
Genetic models
Function of the isoforms
Many studies have been published elucidating functional roles
of tau protein. However, these publications have often based
their findings on the use of one tau isoform, highly expressed
in cell culture models. In the light of the expression differences
observed between the risk and non-risk MAPT haplotypes,
investigations that consider functional differences between
isoforms may offer insight into the disease process. For
example, tau is known to have a role in the regulation of
microtubule dynamic instability [40,41]. It has been shown
that tau isoforms affect this function to different degrees,
with the 4R isoform reducing this instability to a greater
extent than 3R [42,43]. Tau protein has also been shown to
affect axonal transport with tau overexpression perturbing
this process both in vitro [44] and in vivo [45]. Again,
tau’s functional role within this process is modulated by the
different isoforms: the longest tau isoform (2N4R) was shown
to be a less potent inhibitor of both kinesin and dynein than
the shortest tau isoform (0N3R) [46–48]. Furthermore, 4R
tau isoforms affect the trafficking of mitochondria to a greater
extent than 3R isoforms [49].
MAPT genetic models
Great strides towards building better genetic models
for tauopathies came with the first PAC (P1 artificial
chromosome)-transgenic tau mouse model published in 2000
[50]. These transgenic mice were the first mouse models
to express a full-length human MAPT gene driven by
the native human promoter. The human gene is expressed
and transcripts undergo splicing to generate six human tau
isoforms. When crossed on to a mouse tau-null background
[51], the MAPT-PAC tau shows normal localization to the
axons. However, over time, tau relocates to the cell body
and, by 9 months of age, accumulations similar to those
observed in AD can be identified. Although these mice
express a wild-type tau, the level of expression is 4-fold
greater than endogenous. Additionally, this model does not
show the same expression pattern found in human adults
as the mice show more exon 10 − (3R) transcript than the
human control samples [50,51]. This model supports
the theory that an overexpression of a non-mutant tau can
lead to disease pathology either by altered total or specific
isoform expression.
The great advantage of generating transgenic models using
the entire genomic locus is that by their very nature there is
the possibility for studying the effect of non-coding variation
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non-coding variation is limited by the species of the model.
Recent technological advances in the generation of genetic
models will help to circumvent limitations due to species
differences in the expression of genetic loci. One transgenic
model our laboratory has developed relies upon an efficient
viral delivery and expression system for genomic DNA
loci >100 kb in size, which we have termed the iBAC,
or infectious bacterial artificial chromosome, based on
herpes simplex virus type 1 amplicon vectors [52]. We have
successfully used the iBAC system to express the complete
MAPT locus, under the physiological control of its native
promoter, in neuronal culture models [53]. Another approach
studies endogenous MAPT in human stem cells. It has already
been demonstrated that differentiated embryonic human
stem cells show a similar pattern of tau expression to
human post-mortem samples [54]. There is therefore great
scope for future in vitro studies of how MAPT locus
polymorphisms may affect tau physiology and pathology
using human induced pluripotent cells from donors of
differing genotypes [55].
Conclusions
It is clear that the MAPT locus has a key role in a
variety of neurodegenerative disorders and that future work
must seek to elucidate the interaction of the genetics with
functional disease outcomes. In the light of the increasing
body of evidence demonstrating a difference in expression
and alternative splicing between risk and non-risk haplotypes,
it is vital that these future scientific endeavours consider the
role of different tau isoforms in disease mechanisms using
models that allow the investigation of a whole genomic locus.
Funding
We thank Alzheimer’s Research UK and CurePSP for their generous
funding. T.M.C. is funded by the Sir Terry Pratchett Research
Fellowship from Alzheimer’s Research UK.
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Received 6 March 2012
doi:10.1042/BST20120063