Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the
cis
-element, methylation of the
MAPT
gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413]
INTRODUCTION
Tau is a microtubule-associated protein that is abundant in the brain, particularly in neurons. This protein is primarily located in axons, where it binds to microtubules to stabilize these structures and support axonal transport
(1)
. In pathological conditions, the tau protein commonly aggregates to form neurofibrillary tangles – as seen in Alzheimer’s disease (AD) – pick bodies in Pick’s disease (PiD), and tau inclusions, such as in corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease (AGD), frontotemporal dementia (FTD), and myotonic dystrophy type 1 (DM1)
(2
-
6)
. These disorders are collectively known as tauopathies due to their distinct tau pathologies, but the most advanced understanding of the mechanisms underlying tau pathology pertains to AD.
Post-translational modifications, such as hyperphosphorylation, acetylation, and truncation result in tau proteins losing their binding affinity with the microtubule, which, in turn, allows them to become self-aggregated
(7)
. Subsequently, the instability of the neuronal cytoskeleton due to a lack of bound tau proteins in conjunction with the toxicity of tau oligomers leads to neurodegeneration
(8)
. Furthermore, this process can spread into adjacent or connected neurons via synaptic connections
(9)
, which explains the characteristic progressive pattern of tau pathologies
(6)
. Therefore, a majority of therapeutic strategies aimed at treating tauopathies target reductions in tau toxicity at the protein level via decreased phosphorylation, enhanced clearance, and inhibition of the aggregation of tau proteins
(10)
.
In contrast, therapies aimed at altering tau transcription are less common. Based on the alternative splicing of exons 2, 3, and/or 10 in the
MAPT
gene, tau proteins may be present in six isoforms in the human brain
(11)
. Furthermore, the appearance of tau isoforms differs according to age and brain region
(11)
, which is important with respect to normal brain development and physiological function. Genetic studies investigating the mis-splicing of tau pre-mRNA have shown that it plays a role in the pathogenesis of PSP, CBD, PiD, AGD, and FTD
(12
,
13)
but progress in terms of understanding this process remains limited and further investigation is required. Thus, the present paper aimed to review recent knowledge regarding tau RNA splicing and examine the role of this process in neurodegenerative disorders.
TAU ALTERNATIVE SPLICING AND ISOFORM-SPECIFIC FUNCTIONS
The tau protein is encoded from the
MAPT
gene, which is located at chromosome 17q21
(14)
. There are 16 exons in the
MAPT
gene and exons 2, 3, 4A, 6, 8, and 10 can be alternatively spliced
(11)
. Exons 4A, 6, and 8 are not transcribed in the brain; thus, six isoforms are produced in the brain through different combinations of the splicing of exons 2, 3, and/or 10 (
Fig. 1
). Exons 2 and 3 are translated into the N1 and N2 aspects of the N-terminal projection domain, respectively
(15)
, which play important roles in signal transduction and membrane interactions
(16
,
17)
. The encoding region of exon 10 is the second aspect of the C-terminal microtubule-binding repeat domain, R2, and the resulting tau proteins become either 3R or 4R tau, which differ in the number of repeats depending on the splicing of exon 10
(15)
. Because the microtubule-binding repeat domain of tau is its binding site to a microtubule
(18)
, it is essential for the ability of the tau protein to maintain the stability, and regulate the dynamics, of microtubules
(19)
, as well as to support axonal transport
(1)
.
Tau protein isoforms in the human brain. Six tau isoforms are present in the human brain through different combinations of the splicing of exons 2, 3, and/or 10. The aspects of the N-terminal projection domain, N1 (green) and N2 (blue), are produced from exons 2 and 3, respectively. Exon 10 encodes the second aspect of the microtubule-binding repeat domain, R2 (red). Depending on the presence of the R2 domain, tau proteins become either 3R or 4R tau.
The difference in the number of repeats determines the strength of the binding of the tau protein to microtubules; 4R tau binds to microtubules more tightly than 3R tau, which is better for stabilizing the microtubule
(20)
, but the extra repeat makes it more likely that 4R tau will aggregate
(21
,
22)
. Additionally, the dynamics of both retrograde and anterograde axonal transport are higher for the 3R isoform than the 4R isoform
(23)
. The tau isoform-dependent differences in microtubule-binding capacity and axonal transport may explain the benefits of changes in tau isoforms during various developmental stages; 3R tau is the main isoform present in the fetal stage, during which the dynamic nature of the axon is an important requirement for synaptogenesis and establishing neural pathways
(24)
. On the other hand, the overall ratio of 3R to 4R in the mature human brain is maintained at 1:1
(11)
even though the relative amounts of these isoforms vary according to brain region and cell type. For example, granule cells in the hippocampus only express the 3R tau isoform
(24
,
25)
and this difference is thought to provide the cells in this region with a particular resistance or susceptibility to specified tauopathies
(25
-
27)
.
Alternative splicing of the tau protein can also occur at exons 2 and 3 to produce the 0N, 1N, and 2N tau isoforms, which differ in the number of amino-terminal (N-terminal) inserts. Interestingly, exon 3 is spliced only when exon 2 is present
(11
,
13)
; thus, the 1N isoform is produced from a combination of exon 2+/exon3− but not from exon2−/exon 3+. The relative amounts of the N-terminal isoforms are regulated in the human adult brain such that the 2N isoform is the least expressed while the 1N isoform is the most abundant
(28)
. This difference does not seem to have a direct impact on microtubule assembly
(15)
but it was recently suggested that the N-terminal projection domain plays an active role during the regulation of microtubule stabilization
(29)
. When the tau protein is truncated at Gln124 in the N-terminal due to the deletion of repeat inserts, there is an increase in its binding affinity to the microtubule compared to the full-length tau protein
(29)
.
The 1N isoform, which contains an N1 insert from exon 2, enhances the self-aggregating tendency of the tau protein
(30)
while the N2 insert from exon 3, which has an additional N-terminal domain, attenuates the aggregation-promoting effects of the N1 insert
(30)
. The N-terminal repeat inserts interact with various molecules in the human brain that are involved in synaptic signaling, energy metabolism, and cytoskeletal function. When the interaction proteins were analyzed according to the individual N-terminal inserts using bioinformatics with biological process enrichment, the N2 insert was shown to interact with several molecules related to neurodegenerative disorders including 14-3-3
zeta
, ApoA1, ApoE, synaptotagmin, and syntaxin 1B
(31)
. These findings suggest that the N0, N1, and N2 isoforms behave differently under different physiological and pathological conditions; thus, it is possible that the mis-splicing of exons 2 and 3 contributes to various tauopathies. However, direct evidence demonstrating this relationship is lacking and more intensive studies are needed to further elucidate this issue.
MECHANISMS UNDERLYING THE SPLICING REGULATION OF THE TAU TRANSCRIPT
The assembly of the spliceosome, which is a multi-protein complex to the
cis
-acting pre-mRNA sequence, is an essential step in the splicing process
(32)
. The
cis
-acting element is a short and diverse sequence that can be located in either the exon or intron; its influence differs depending on location and sequence. Based on their effects on splicing,
cis
-elements are classified as splicing enhancers, silencers, or modulators
(32)
. The
MAPT
gene mutations that are close to, or within, the
cis
-acting elements result in FTD with Parkinsonism linked to chromosome 17 (FTDP-17) and other tauopathies associated with mis-splicing
(12)
. Many serine- and arginine-rich (SR) proteins possess a specific affinity for the cis-element of the
MAPT
gene and regulate the splicing of exon 10
(33)
(
Table 1
). In addition to these proteins, several non-SR proteins also play a role in the splicing of exon 10. For example, RNA-binding motif protein 4 (RBM4)
(34)
, Tra2β
(35)
, RNA helicase p68
(36)
, heterogeneous nuclear (hn) RNP E2 and E3
(37
,
38)
, and CUG-binding protein (CELF)
(39
,
40)
are known to be involved. The variants that depend on the
cis
-element and splicing factors likely act cooperatively to determine the efficacy and direction of the splicing of exon 10 in the
MAPT
gene.
Factors regulating the splicing of exon 10 ofMAPTpre-mRNA
DYRK1, dual-specificity tyrosine-phosphorylated and regulated kinase 1A; E, exon; I, intron; PTBP2, polypyrimidine tract-binding protein 2; RBM4, RNA-biding motif protein 4; SF, splicing factors; PKA, cyclic AMP-dependent protein kinase; PSF, polypyrimidine tract binding protein associated splicing factor; SWAP, suppressor of white apricot protein. *Variable depending on cell type (45). Summarized from the literature (12, 13, 33-48).
The regulation of alternative splicing processes is further complicated by variables arising from the altered expression and activity of splicing factors following modifications at the transcriptional, post-transcriptional, and post-translational levels. miRNA-132 is known to regulate the splicing of exon 10 via the inhibition of the expression of the PTBP2 protein, which is a splicing factor
(41)
. Additionally, various kinases, including cyclic AMP-dependent protein kinase (PKA)
(42
,
43)
, dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1)
(44
-
47)
, and GSK-3β
(48)
, regulate the activities of splicing proteins via phosphorylation and, thereby, exon 10 splicing. This issue has been well described in a recent review article
(33)
. From an epigenetic point of view, the regulation of splicing by DNA methylation may also be involved in this process
(26)
. The speed of RNA polymerase II during the elongation and reposition of splicing factors to alternative exons by heterochromatin protein 1 (HP1) is controlled by DNA methylation
(49)
. Considering that a CpG island is present in exon 9, it is the possible that DNA methylation plays a role in regulating the alternative splicing of the
MAPT
gene
(26)
but there is a lack of studies investigating this issue.
Relative to the processes associated with the splicing of exon 10, the regulatory mechanisms underlying the alternative splicing of exons 2 and 3 are less clear. Several spliceosomal proteins involved in exon 10 splicing also regulate exon 3 splicing. For example, SRSF1, SRSF2, SRSF3, SRSF9, SWAP, Tra2β, and Nova 1 decrease the inclusion of exon 3 while SRSF4 and SFSF6 enhance its inclusion
(13)
. According to the linkage disequilibrium of nucleotide polymorphisms, the
MAPT
gene has two major haplotypes, H1 and H2, and the alternative splicing processes exhibit different patterns depending on haplotype. The H2 haplotype of the
MAPT
gene tends to include the exon 3
(27
,
50)
. Furthermore, the transcriptional efficacy and DNA methylation patterns of the H1 and H2 haplotypes, which are described in detail below, also differ. In conjunction, the differential roles of the haplotypes are thought to contribute to haplotype-dependent tauopathies
(51
,
52)
.
TAU MIS-SPLICING AND NEURODEGENERATIVE DISORDERS
- Genetic mutations in theMAPTgene
Genetic mutations in the
MAPT
gene can result in PSP, CBD, PiD, and FTDP-17. These pathogenic mutations of the
MAPT
gene are primarily located within exons 9-13 (
Fig. 2
) but are not limited to point missense and deletional mutations in exons. In fact, silent, and even intronic, mutations can induce a tauopathy
(12)
. The boundary of exon10/intron 10 includes an RNA sequence that forms a stem-loop due to self-complementary bindings at the stem and this region is a hot spot for
MAPT
gene mutations. Most of the pathogenic intronic mutations are clustered in the stem-loop where mutations induce the mis-splicing of exon 10 by decreasing stem-loop stability, which in turn increases the inclusion of exon 10. Subsequently, the altered RNA structure enhances the accessibility of the spliceosome to this region and results in mis-splicing
(36
,
53)
. Ultimately, these intronic mutations clinically manifest as FTD in most cases, via increases in either the 3R or 4R tau isoform; IVS9-10 G > T, IVS10+3 G > A, IVS10+11 T > C, IVS10+12 C > T, IVS10+13 A > G, IVS10+14 C > T, IVS10+15 A > C, and IVS10+16 C > T tend to increase 4R tau
(53
-
58)
while IVS9-15 T > C, IVS10+4 A > C, and IVS10+19 C > G inhibit the inclusion of exon 10 and increase 3R tau
(59
,
60)
. L284L (CTT to CTC), N296N (AAT to AAC), and S305S (AGT to AGC) are silent point mutations that result in tauopathy, FTD, or PSP
(61
-
63)
. Their location is close to the exon 10/intron 10 interface and increases the 4R tau isoform by enhancing the inclusion of exon 10. The mechanisms underlying the neurodegeneration caused by perturbations of the 3R-4R tau balance remain elusive but the isoform-dependent differences in the propensity for aggregation are thought to behave pathologically when the 3R:4R balance is disordered
(64)
.
Causative MAPT gene mutations associated with tauopathies. The differential impacts of the causative MAPT gene mutations on tau-isoform specific pathologies can be demonstrated in three ways: 1) tau mis-splicing that increases either 3R tau (green line or arrowhead) or 2) 4R tau isoforms (blue line) and 3) 4R tau isoform-distinct pathologies without mis-splicing (blue dotted line).
Changes in the tau protein sequence due to exonic missense and deletion mutations do not always cause alterations in the ratio of the 3R and 4R tau isoforms. Instead, amino acid substitutions alter the tau structure into pathological forms
(65)
. Interestingly, despite the fact that exon 10 is not mis-spliced, distinctive isoform-specific pathologies have been noted. R5H
(66)
, R5L
(67)
, I260V
(68)
, P301L
(57)
, G303V
(69)
, and K317N
(70)
result in an increased propensity for aggregation and filament formation of 4R tau proteins without altering the 3R:4R tau ratio. The dominance of 4R tau isoform-specific pathologies in the absence of mis-splicing suggests that the 4R tau isoform is susceptible to becoming pathological following a mutation of the
MAPT
gene.
It is rare that pathogenic
MAPT
gene mutations will lead to the mis-splicing of exons 2 and 3. The E342V mutation in exon 12 causes an increased splicing of exon 10, but the reduced inclusion of exons 2 and 3
(71)
, and the tau inclusions in the R5L mutation of exon 1, primarily consist of 4R tau with either no insert or the N1 insert (0N4R or 1N4R)
(67)
. The possible role of an altered number of N-terminal inserts in tauopathies can be considered based on the biological effects of N-terminal inserts in modifying tau aggregation and signaling pathways
(16
,
17
,
30
,
31)
. However, further studies are needed to clarify this issue.
- Without genetic mutations in theMAPTgene
Isoform-specific tau pathologies are also observed in the absence of
MAPT
gene mutations in sporadic cases of PSP, CBD, PiD, AGD (4R tau), PiB (3R tau), and FTD (mixture of 3R and/or 4R tau). Overt tau mis-splicing can occur in these sporadic cases
(72)
and it has been suggested that the preference of haplotype for specified splicing is the mechanism underlying the alterations in alternative splicing
(12)
. The H1 haplotype, particularly the H1c sub-haplotype, is thought to increase the risk of PSP and CBD by increasing exon 10 splicing
(73
-
76)
. However, a recent study that included a large sample size of brains found opposite results for the H1 haplotype but a protective influence of the H2 haplotype against PSP, CBD, and PD via increases in exon 3
(27)
, as has been previously suggested
(50)
. Various combinations of haplotype-dependent genetic variations are known to modulate DNA methylation
(77)
, transcription, and mRNA splicing
(75
,
78)
. Thus, the complicated interactions of these factors are thought to cooperatively determine the direction of tau exon splicing.
Differences in the expression and activity of spliceosomal proteins result in aberrant splicing and contribute to the manifestation of a tauopathy. In PSP patients, increases in SRSF2 and Tra2β in the locus coeruleus are associated with increases in the 4R tau isoform
(79)
. And the decreases of miRNA-132 thereby increase of PTBP2 was shown to enhance 4R tau pathology in the PSP brain
(41)
. The pathogenic role of tau mis-splicing in AD is controversial and has been previously reviewed
(12)
, but recent reports have raised the possibility that its contribution to AD is due to increased DYRK2 activity in the brain, which continuously increases 3R tau expression and tau pathology
(44)
.
Recent, accumulating evidence suggests the there is a discriminative relationship between tau isoforms and neurodegenerative disorders, which means that certain tau isoforms are more vulnerable to specific pathogenic factors and explains why there are isoform-specific pathologies and regional selectivity in tauopathies
(27
,
80)
. The relative ratio of tau isoforms varies across cell types and brain regions
(27
,
80)
and specified cells and/or regions that contain greater amounts of specified tau isoforms tend to be more easily affected by corresponding disorders
(7
,
81)
. For example, the quantity of the 4R tau isoform is higher in the globus pallidum, which may explain why this region is particularly affected by the pathological processes of PSP
(81)
. Likewise, granule cells in the hippocampus exclusively express 3R tau isoforms and the 3R tau-positive pick body is most abundant in PiD patients
(25)
.
Tau mRNA mis-splicing may develop as a co-phenomenon of widespread RNA dysregulation during neurodegenerative processes. As a prime example, 4R tau aggregates have been identified in the striatum and cortex of Huntington’s disease (HD) patients
(82)
while 0N3R tau inclusions are found in DM1 patients
(83
,
84)
. DM1 and HD are caused by CTG repeats in the
DMPK
gene
(85)
and CAG repeats in the
HTT
gene
(86)
, respectively. In these disorders, tau mRNA mis-splicing is due to impairments in normal alternative splicing that occur subsequent to the sequestration of splicing factors by the abnormally expanded CUG transcripts
(82
,
87)
. Tau mis-splicing in conjunction with isoform-specific tau pathologies is thought to induce pathogenic cognitive deficits and behavioral changes
(82
,
84)
. The toxic aggregates of fused in sarcoma (FUS) and TAR DNA-binding protein (TDP-43) in the cytoplasm are observed in patients with amyotrophic lateral sclerosis (ALS) and FTD
(88
,
89)
. Furthermore, there are mutations in the corresponding genes,
FUS
and
TARDBP
, respectively, in familial ALS and FTD
(90
,
91)
, which demonstrates the pathogenic roles of FUS and TDP-43 in neurodegenerative disorders. FUS and TDP-43 are nuclear proteins involved in RNA processes such as transcription and the splicing of multiple genes
(92
,
93)
. In pathological conditions, the inclusion of FUS and TDP-43 as RNA processing proteins results in impaired physiological processes. The altered splicing of exons 3 and 10 in tau pre-mRNA has been observed in FUS-related proteinopathies
(94)
and it is thought that decreases in the propensity of FUS to directly bind to tau pre-mRNA alters the regulation of the splicing of exons 3 and 10
(94)
. In contrast, the TDP-43 proteinopathy does not impair tau pre-mRNA alternative splicing
(95)
despite the extensive RNA mis-processing exerted by the aggregation of TDP-43 proteins, which hinders its normal function as an RNA binding protein
(96)
. Thus, the perturbation of tau pre-mRNA processing by neurodegenerative disorders is determined by the types of proteinopathies and RNAopathies. Future investigations will provide a clearer understanding of the relationship between tau mis-splicing and individual neurodegenerative disorders.
CONCLUSIONS
The pathogenic contributions of tau mis-splicing are likely highly correlated with the manifestation of neurodegenerative disorders via tauopathies as well as non-tau proteinopathies. This type of mis-splicing leads to an imbalance of tau isoforms that impairs isoform-specific, normal physiological function and enhances vulnerability to pathological processes. Current understanding of the relationship between tau mis-splicing and neurodegenerative disorders is originated from cases of
MAPT
gene mutations, which widened existing knowledge about the mechanisms underlying tau splicing. Several trials corrected exon 10 mis-splicing in
MAPT
gene mutations using small molecules
(97)
, modified antisense oligonucleotides
(98)
, or spliceosome-mediated RNA trans-splicing
(99)
but none of these studies progressed to clinical trials.
A variety of complex factors are involved in the regulation of the alternative splicing of tau. Differences in the integrity of the cis-element, methylation of the
MAPT
gene, genetic polymorphisms, quantity and activity of spliceosomal proteins, and patency of other RNA binding proteins appear to cooperatively impact alternative tau splicing. In sporadic cases of tauopathy that present with tau-isoform specific pathologies, these variables operate together to influence tau mis-splicing; thus, therapeutic strategies should be much more delicately designed. Current understanding of tau mis-splicing remains limited, especially in terms of its pathological role in non-tau proteinopathies, RNAopathies, and sporadic cases. Further studies should be performed to develop efficient therapeutic strategies for the treatment of these disorders.
Acknowledgements
This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1943).
Dixit R
,
Ross JL
,
Goldman YE
,
Holzbaur EL
(2008)
Differential regulation of dynein and kinesin motor proteins by tau.
Science
319
1086 -
1089
DOI : 10.1126/science.1152993
Munoz DG
,
Ferrer I
(2008)
Neuropathology of hereditary forms of frontotemporal dementia and parkinsonism.
Handb Clin Neurol
89
393 -
414
Togo T
,
Sahara N
,
Yen SH
(2002)
Argyrophilic grain disease is a sporadic 4-repeat tauopathy.
J Neuropathol Exp Neurol
61
547 -
556
DOI : 10.1093/jnen/61.6.547
Arai T
,
Ikeda K
,
Akiyama H
(2001)
Distinct isoforms of tau aggregated in neurons and glial cells in brains of patients with Pick's disease, corticobasal degeneration and progressive supranuclear palsy.
Acta Neuropathol
101
167 -
173
Sergeant N
,
Sablonniere B
,
Schraen-Maschke S
(2001)
Dysregulation of human brain microtubuleassociated tau mRNA maturation in myotonic dystrophy type 1.
Hum Mol Genet
10
2143 -
2155
DOI : 10.1093/hmg/10.19.2143
Braak H
,
Braak E
(1991)
Neuropathological stageing of Alzheimer-related changes.
Acta Neuropathol
82
239 -
259
DOI : 10.1007/BF00308809
Ballatore C
,
Lee VM
,
Trojanowski JQ
(2007)
Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.
Nat Rev Neurosci
8
663 -
672
DOI : 10.1038/nrn2194
Sanders DW
,
Kaufman SK
,
DeVos SL
(2014)
Distinct tau prion strains propagate in cells and mice and define different tauopathies.
Neuron
82
1271 -
1288
DOI : 10.1016/j.neuron.2014.04.047
Brunden KR
,
Trojanowski JQ
,
Lee VM
(2009)
Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies.
Nat Rev Drug Discov
8
783 -
793
DOI : 10.1038/nrd2959
Goedert M
,
Spillantini MG
,
Jakes R
,
Rutherford D
,
Crowther RA
(1989)
Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease.
Neuron
3
519 -
526
DOI : 10.1016/0896-6273(89)90210-9
Niblock M
,
Gallo JM
(2012)
Tau alternative splicing in familial and sporadic tauopathies.
Biochem Soc Trans
40
677 -
680
DOI : 10.1042/BST20120091
Andreadis A
(2005)
Tau gene alternative splicing: expression patterns, regulation and modulation of function in normal brain and neurodegenerative diseases.
Biochim Biophys Acta
1739
91 -
103
DOI : 10.1016/j.bbadis.2004.08.010
Neve RL
,
Harris P
,
Kosik KS
,
Kurnit DM
,
Donlon TA
(1986)
Identification of cDNA clones for the human microtubuleassociated protein tau and chromosomal localization of the genes for tau and microtubuleassociated protein 2.
Brain Res
387
271 -
280
DOI : 10.1016/0169-328X(86)90033-1
Goedert M
,
Jakes R
(1990)
Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization.
EMBO J
9
4225 -
4230
Brandt R
,
Leger J
,
Lee G
(1995)
Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain.
J Cell Biol
131
1327 -
1340
DOI : 10.1083/jcb.131.5.1327
Chen J
,
Kanai Y
,
Cowan NJ
,
Hirokawa N
(1992)
Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons.
Nature
360
674 -
677
DOI : 10.1038/360674a0
Feinstein SC
,
Wilson L
(2005)
Inability of tau to properly regulate neuronal microtubule dynamics: a loss-of-function mechanism by which tau might mediate neuronal cell death.
Biochim Biophys Acta
1739
268 -
279
DOI : 10.1016/j.bbadis.2004.07.002
Goode BL
,
Chau M
,
Denis PE
,
Feinstein SC
(2000)
Structural and functional differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenetative disease.
J Biol Chem
275
38182 -
38189
DOI : 10.1074/jbc.M007489200
Adams SJ
,
DeTure MA
,
McBride M
,
Dickson DW
,
Petrucelli L
(2010)
Three repeat isoforms of tau inhibit assembly of four repeat tau filaments.
PLoS One
5
e10810 -
DOI : 10.1371/journal.pone.0010810
Panda D
,
Samuel JC
,
Massie M
,
Feinstein SC
,
Wilson L
(2003)
Differential regulation of microtubule dynamics by three- and four-repeat tau: implications for the onset of neurodegenerative disease.
Proc Natl Acad Sci U S A
100
9548 -
9553
DOI : 10.1073/pnas.1633508100
Stoothoff W
,
Jones PB
,
Spires-Jones TL
(2009)
Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport.
J Neurochem
111
417 -
427
DOI : 10.1111/j.1471-4159.2009.06316.x
Goedert M
,
Spillantini MG
,
Potier MC
,
Ulrich J
,
Crowther RA
(1989)
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
8
393 -
399
Hof PR
,
Bouras C
,
Perl DP
,
Morrison JH
(1994)
Quantitative neuropathologic analysis of Pick's disease cases: cortical distribution of Pick bodies and coexistence with Alzheimer's disease.
Acta Neuropathol
87
115 -
124
DOI : 10.1007/BF00296179
Caillet-Boudin ML
,
Buee L
,
Sergeant N
,
Lefebvre B
(2015)
Regulation of human MAPT gene expression.
Mol Neurodegener
10
28 -
DOI : 10.1186/s13024-015-0025-8
Trabzuni D
,
Wray S
,
Vandrovcova J
(2012)
MAPT expression and splicing is differentially regulated by brain region: relation to genotype and implication for tauopathies.
Hum Mol Genet
21
4094 -
4103
DOI : 10.1093/hmg/dds238
Boutajangout A
,
Boom A
,
Leroy K
,
Brion JP
(2004)
Expression of tau mRNA and soluble tau isoforms in affected and non-affected brain areas in Alzheimer's disease.
FEBS Lett
576
183 -
189
DOI : 10.1016/j.febslet.2004.09.011
Derisbourg M
,
Leghay C
,
Chiappetta G
(2015)
Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms.
Sci Rep
5
9659 -
DOI : 10.1038/srep09659
Zhong Q
,
Congdon EE
,
Nagaraja HN
,
Kuret J
(2012)
Tau isoform composition influences rate and extent of filament formation.
J Biol Chem
287
20711 -
20719
DOI : 10.1074/jbc.M112.364067
Liu C
,
Song X
,
Nisbet R
,
Götz J
(2016)
Co-immunoprecipitation with tau isoform-specific antibodies reveals distinct protein interactions, and highlights a putative role for 2N tau in disease.
J Biol Chem
291
8173 -
8188
DOI : 10.1074/jbc.M115.641902
Kar A
,
Havlioglu N
,
Tarn WY
,
Wu JY
(2006)
RBM4 interacts with an intronic element and stimulates tau exon 10 inclusion.
J Biol Chem
281
24479 -
24488
DOI : 10.1074/jbc.M603971200
Jiang Z
,
Tang H
,
Havlioglu N
(2003)
Mutations in tau gene exon 10 associated with FTDP-17 alter the activity of an exonic splicing enhancer to interact with Tra2 beta.
J Biol Chem
278
18997 -
19007
DOI : 10.1074/jbc.M301800200
Kar A
,
Fushimi K
,
Zhou X
(2011)
RNA helicase p68 (DDX5) regulates tau exon 10 splicing by modulating a stem-loop structure at the 5' splice site.
Mol Cell Biol
31
1812 -
1821
DOI : 10.1128/MCB.01149-10
Wang Y
,
Gao L
,
Tse SW
,
Andreadis A
(2010)
Heterogeneous nuclear ribonucleoprotein E3 modestly activates splicing of tau exon 10 via its proximal downstream intron, a hotspot for frontotemporal dementia mutations.
Gene
451
23 -
31
DOI : 10.1016/j.gene.2009.11.006
Broderick J
,
Wang J
,
Andreadis A
(2004)
Heterogeneous nuclear ribonucleoprotein E2 binds to tau exon 10 and moderately activates its splicing.
Gene
331
107 -
114
DOI : 10.1016/j.gene.2004.02.005
Dhaenens CM
,
Tran H
,
Frandemiche ML
(2011)
Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing.
Biochim Biophys Acta
1812
732 -
742
DOI : 10.1016/j.bbadis.2011.03.010
Chapple JP
,
Anthony K
,
Martin TR
,
Dev A
,
Cooper TA
,
Gallo JM
(2007)
Expression, localization and tau exon 10 splicing activity of the brain RNA-binding protein TNRC4.
Hum Mol Genet
16
2760 -
2769
DOI : 10.1093/hmg/ddm233
Smith PY
,
Delay C
,
Girard J
(2011)
MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy.
Hum Mol Genet
20
4016 -
4024
DOI : 10.1093/hmg/ddr330
Chen C
,
Jin N
,
Qian W
(2014)
Cyclic AMP-dependent protein kinase enhances SC35-promoted Tau exon 10 inclusion.
Mol Neurobiol
49
615 -
624
DOI : 10.1007/s12035-013-8542-3
Gu J
,
Shi J
,
Wu S
(2012)
Cyclic AMP-dependent protein kinase regulates 9G8-mediated alternative splicing of tau exon 10.
FEBS Lett
586
2239 -
2244
DOI : 10.1016/j.febslet.2012.05.046
Jin N
,
Yin X
,
Gu J
(2015)
Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I: A MOLECULAR MECHANISM LINKED TO TAU PATHOLOGY IN ALZHEIMER DISEASE.
J Biol Chem
290
15219 -
15237
DOI : 10.1074/jbc.M115.645507
Qian W
,
Liang H
,
Shi J
(2011)
Regulation of the alternative splicing of tau exon 10 by SC35 and Dyrk1A.
Nucleic Acids Res
39
6161 -
6171
DOI : 10.1093/nar/gkr195
Shi J
,
Zhang T
,
Zhou C
(2008)
Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome.
J Biol Chem
283
28660 -
28669
DOI : 10.1074/jbc.M802645200
Chen KL
,
Yuan RY
,
Hu CJ
,
Hsu CY
(2010)
Amyloidbeta peptide alteration of tau exon-10 splicing via the GSK3beta-SC35 pathway.
Neurobiol Dis
40
378 -
385
DOI : 10.1016/j.nbd.2010.06.013
Lev Maor G
,
Yearim A
,
Ast G
(2015)
The alternative role of DNA methylation in splicing regulation.
Trends Genet
31
274 -
280
DOI : 10.1016/j.tig.2015.03.002
Caffrey TM
,
Wade-Martins R
(2007)
Functional MAPT haplotypes: bridging the gap between genotype and neuropathology.
Neurobiol Dis
27
1 -
10
DOI : 10.1016/j.nbd.2007.04.006
Pittman AM
,
Myers AJ
,
Abou-Sleiman P
(2005)
Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration.
J Med Genet
42
837 -
846
DOI : 10.1136/jmg.2005.031377
McCarthy A
,
Lonergan R
,
Olszewska DA
(2015)
Closing the tau loop: the missing tau mutation.
Brain
138
3100 -
3109
DOI : 10.1093/brain/awv234
Malkani R
,
D’Souza I
,
Gwinn-Hardy K
,
Schellenberg GD
,
Hardy J
,
Momeni P
(2006)
A MAPT mutation in a regulatory element upstream of exon 10 causes frontotemporal dementia.
Neurobiol Dis
22
401 -
403
DOI : 10.1016/j.nbd.2005.12.001
Kowalska A
,
Hasegawa M
,
Miyamoto K
(2002)
A novel mutation at position +11 in the intron following exon 10 of the tau gene in FTDP-17.
J Appl Genet
43
535 -
543
Hutton M
,
Lendon CL
,
Rizzu P
(1998)
Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17.
Nature
393
702 -
705
DOI : 10.1038/31508
Spillantini MG
,
Murrell JR
,
Goedert M
,
Farlow MR
,
Klug A
,
Ghetti B
(1998)
Mutation in the tau gene in familial multiple system tauopathy with presenile dementia.
Proc Natl Acad Sci U S A
95
7737 -
7741
DOI : 10.1073/pnas.95.13.7737
Stanford PM
,
Shepherd CE
,
Halliday GM
(2003)
Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia.
Brain
126
814 -
826
DOI : 10.1093/brain/awg090
Stanford PM
,
Halliday GM
,
Brooks WS
(2000)
Progressive supranuclear palsy pathology caused by a novel silent mutation in exon 10 of the tau gene: expansion of the disease phenotype caused by tau gene mutations.
Brain
123
880 -
893
DOI : 10.1093/brain/123.5.880
D’Souza I
,
Poorkaj P
,
Hong M
(1999)
Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements.
Proc Natl Acad Sci U S A
96
5598 -
5603
DOI : 10.1073/pnas.96.10.5598
Umeda T
,
Yamashita T
,
Kimura T
(2013)
Neurodegenerative disorder FTDP-17-related tau intron 10 +16C → T mutation increases tau exon 10 splicing and causes tauopathy in transgenic mice.
Am J Pathol
183
211 -
225
DOI : 10.1016/j.ajpath.2013.03.015
Ghetti B
,
Oblak AL
,
Boeve BF
,
Johnson KA
,
Dickerson BC
,
Goedert M
(2015)
Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging.
Neuropathol Appl Neurobiol
41
24 -
46
DOI : 10.1111/nan.12213
Hayashi S
,
Toyoshima Y
,
Hasegawa M
(2002)
Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation.
Ann Neurol
51
525 -
530
DOI : 10.1002/ana.10163
Poorkaj P
,
Muma NA
,
Zhukareva V
(2002)
An R5L tau mutation in a subject with a progressive supranuclear palsy phenotype.
Ann Neurol
52
511 -
516
DOI : 10.1002/ana.10340
Ros R
,
Thobois S
,
Streichenberger N
(2005)
A new mutation of the tau gene, G303V, in early-onset familial progressive supranuclear palsy.
Arch Neurol
62
1444 -
1450
DOI : 10.1001/archneur.62.9.1444
Tacik P
,
DeTure M
,
Lin WL
(2015)
A novel tau mutation, p.K317N, causes globular glial tauopathy.
Acta Neuropathol
130
199 -
214
DOI : 10.1007/s00401-015-1425-0
de Silva R
,
Lashley T
,
Strand C
(2006)
An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies.
Acta Neuropathol
111
329 -
340
DOI : 10.1007/s00401-006-0048-x
Baker M
,
Litvan I
,
Houlden H
(1999)
Association of an extended haplotype in the tau gene with progressive supranuclear palsy.
Hum Mol Genet
8
711 -
715
DOI : 10.1093/hmg/8.4.711
Pittman AM
,
Fung HC
,
de Silva R
(2006)
Untangling the tau gene association with neurodegenerative disorders.
Hum Mol Genet
15
(2)
R188 -
195
DOI : 10.1093/hmg/ddl190
Rademakers R
,
Melquist S
,
Cruts M
(2005)
High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy.
Hum Mol Genet
14
3281 -
3292
DOI : 10.1093/hmg/ddi361
Houlden H
,
Baker M
,
Morris HR
(2001)
Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype.
Neurology
56
1702 -
1706
DOI : 10.1212/WNL.56.12.1702
Li Y
,
Chen JA
,
Sears RL
(2014)
An epigenetic signature in peripheral blood associated with the haplotype on 17q21.31, a risk factor for neurodegenerative tauopathy.
PLoS Genet
10
e1004211 -
DOI : 10.1371/journal.pgen.1004211
Sobrido MJ
,
Miller BL
,
Havlioglu N
(2003)
Novel tau polymorphisms, tau haplotypes, and splicing in familial and sporadic frontotemporal dementia.
Arch Neurol
60
698 -
702
DOI : 10.1001/archneur.60.5.698
Bruch J
,
Xu H
,
De Andrade A
,
Hoglinger G
(2014)
Mitochondrial complex 1 inhibition increases 4-repeat isoform tau by SRSF2 upregulation.
PLoS One
9
e113070 -
DOI : 10.1371/journal.pone.0113070
McMillan P
,
Korvatska E
,
Poorkaj P
(2008)
Tau isoform regulation is region- and cell-specific in mouse brain.
J Comp Neurol
511
788 -
803
DOI : 10.1002/cne.21867
Fernandez-Nogales M
,
Cabrera JR
,
Santos-Galindo M
(2014)
Huntington's disease is a four-repeat tauopathy with tau nuclear rods.
Nat Med
20
881 -
885
DOI : 10.1038/nm.3617
Jiang H
,
Mankodi A
,
Swanson MS
,
Moxley RT
,
Thornton CA
(2004)
Myotonic dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of muscleblind proteins and deregulated alternative splicing in neurons.
Hum Mol Genet
13
3079 -
3088
DOI : 10.1093/hmg/ddh327
Seznec H
,
Agbulut O
,
Sergeant N
(2001)
Mice transgenic for the human myotonic dystrophy region with expanded CTG repeats display muscular and brain abnormalities.
Hum Mol Genet
10
2717 -
2726
DOI : 10.1093/hmg/10.23.2717
Brook JD
,
McCurrach ME
,
Harley HG
(1992)
Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.
Cell
68
799 -
808
DOI : 10.1016/0092-8674(92)90154-5
The Huntington's Disease Collaborative Research Group
(1993)
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes.
Cell
72
971 -
983
DOI : 10.1016/0092-8674(93)90585-E
Mykowska A
,
Sobczak K
,
Wojciechowska M
,
Kozlowski P
,
Krzyzosiak WJ
(2011)
CAG repeats mimic CUG repeats in the misregulation of alternative splicing.
Nucleic Acids Res
39
8938 -
8951
DOI : 10.1093/nar/gkr608
Deng HX
,
Zhai H
,
Bigio EH
(2010)
FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis.
Ann Neurol
67
739 -
748
Neumann M
,
Sampathu DM
,
Kwong LK
(2006)
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Science
314
130 -
DOI : 10.1126/science.1134108
Gitcho MA
,
Bigio EH
,
Mishra M
(2009)
J. TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy.
Acta Neuropathol
118
633 -
645
DOI : 10.1007/s00401-009-0571-7
Kwiatowski TJ
,
Bosco DA
,
LeClerc AL
(2009)
Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis.
Science
323
1205 -
1208
DOI : 10.1126/science.1166066
Buratti E
,
Dörk T
,
Zuccato E
,
Pagani F
,
Romano M
,
Baralle FE
(2001)
Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping.
EMBO J
20
1774 -
1784
DOI : 10.1093/emboj/20.7.1774
Yang L
,
Embree LJ
,
Hickstein DD
(2000)
TLS-ERG leukemia fusion protein inhibits RNA splicing mediated by serine-arginine proteins.
Mol Cell Biol
20
3345 -
3354
DOI : 10.1128/MCB.20.10.3345-3354.2000
Orozco D
,
Tahirovic S
,
Rentzsch K
,
Schwenk BM
,
Haass C
,
Edbauer D
(2012)
Loss of fused in sarcoma (FUS) promotes pathological Tau splicing.
EMBO Rep
13
759 -
764
DOI : 10.1038/embor.2012.90
Tollervey JR
,
Curk T
,
Rogelj B
(2011)
Characterizing the RNA targets and position-dependent splicing regulation by TDP-43.
Nat Neurosci
14
452 -
458
DOI : 10.1038/nn.2778
Highley JR
,
Kirby J
,
Jansweijer JA
(2014)
Loss of nuclear TDP-43 in amyotrophic lateral sclerosis (ALS) causes altered expression of splicing machinery and widespread dysregulation of RNA splicing in motor neurones.
Neuropathol Appl Neurobiol
40
670 -
685
DOI : 10.1111/nan.12148
Liu Y
,
Rodriguez L
,
Wolfe MS
(2014)
Template-directed synthesis of a small molecule-antisense conjugate targeting an mRNA structure.
Bioorg Chem
54
7 -
11
DOI : 10.1016/j.bioorg.2014.03.001
Kalbfuss B
,
Mabon SA
,
Misteli T
(2001)
Correction of alternative splicing of tau in frontotemporal dementia and parkinsonism linked to chromosome 17.
J Biol Chem
276
42986 -
42993
DOI : 10.1074/jbc.M105113200
Rodriguez-Martin T
,
Anthony K
,
Garcia-Blanco MA
,
Mansfield SG
,
Anderton BH
,
Gallo J-M
(2009)
Correction of tau mis-splicing caused by FTDP-17 MAPT mutations by spliceosome-mediated RNA trans-splicing.
Hum Mol Genet
18
3266 -
3273
DOI : 10.1093/hmg/ddp264