Regulation of tau isoform expression and dementia
Ian D’Souzaa,b, Gerard D. Schellenberga,b,c,*
aGeriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, 1660 S. Columbian Way,
Seattle WA 98108, United States
bDivisions of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle, WA 98195, United States
cDepartments of Neurology and Pharmacology, University of Washington, Seattle WA 98195, United States
Received 17 August 2004; accepted 24 August 2004
Available online 11 September 2004
In the central nervous system (CNS), aberrant changes in tau mRNA splicing and consequently in protein isoform ratios cause abnormal
aggregation of tau and neurodegeneration. Pathological tau causes neuronal loss in Alzheimer’s disease (AD) and a diverse group of
disorders called the frontotemporal dementias (FTD), which are two of the most common forms of dementia and afflict more than 10% of the
elderly population. Autosomal dominant mutations in the tau gene cause frontotemporal dementia with parkinsonism-chromosome 17 type
(FTDP-17). Just over half the mutations affect tau protein function and decrease its affinity for microtubules (MTs) or increase self-
aggregation. The remaining mutations occur within exon 10 (E10) and intron 10 sequences and alter complex regulation of E10 splicing by
multiple mechanisms. FTDP-17 splicing mutations disturb the normally balanced levels of distinct protein isoforms that result in altered
biochemical and structural properties of tau. In addition to FTDP-17, altered tau isoform levels are also pathogenically associated with other
FTD disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration and Pick’s disease; however, the mechanisms remain
undefined and mutations in tau have not been detected. FTDP-17 highlights the association between splicing mutations and the pronounced
variability in pathology as well as phenotype that is characteristic of inherited disorders.
D 2004 Elsevier B.V. All rights reserved.
Keywords: Tau; Dementia
Tau is a phosphoprotein that binds to and stabilizes
microtubules (MTs). This protein is highly expressed in
neuronal axons and at lower levels in glia and also in certain
non-nervous system tissues. Tau binds to tubulin, the protein
building block of MTs, and in vitro polymerization of tubulin
into MTs is stimulated by tau. In neurons, tau is important for
morphogenesis, axonal extension as well as axonal vesicle
and protein transport [1–5]. In adult human brain, six tau
isoforms are expressed from a single gene by alternative
splicing of exons 2, 3 and 10 (Fig. 1) [6–8]. Exons 9–12 each
encode a 31–32-amino-acid MT-binding imperfect repeat
domain. Exon 10 (E10) is an alternatively spliced exon.
When E10 is excluded, the result is a protein with three
microtubule binding repeats (3R tau). When E10 is included,
a fourth MT-binding domain is added to generate four-repeat
excluded and a single isoform is produced (0N3R, Fig. 1). In
human adult brain, balanced splicing of E10 results in a 4R/
3R tau ratio of ~1. Interestingly, only the three E10+ single
isoforms are expressed in adult rodent brain [9,10]. Since 4R
tau binds MTs threefold more strongly and assembles MTs
different tau isoforms in fetal versus adult neurons suggests
different functional requirements for tau–MT interactions in
maintaining the dynamic stability of the neuroskeletal
architecture [11–13]. Tau has numerous phosphorylation
sites, and phosphorylation is developmentally regulated
[14,15]. In the central nervous system (CNS), fetal tau is
more highly phosphorylated than in adult brain. Phosphor-
ylation of tau at proline-directed serine/threonine sites
0925-4439/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
* Corresponding author. Department of Medicine, Division of Neurol-
ogy, University of Washington, RG-27, Seattle, WA 98195, United States.
Tel.: +1 206 543 2340; fax: +1 206 685 8100.
E-mail address: firstname.lastname@example.org (G.D. Schellenberg).
Biochimica et Biophysica Acta 1739 (2005) 104–115
reduces the affinity of tau for MTs, thus regulating MT
In a number of neurodegenerative diseases, tau aggre-
gates in neurons forming either paired helical filaments
(PHF) or straight filaments that form neurofibrillary tangles
(NFT’s) [20,21]. In a subset of these disorders, similar tau
aggregates also accumulate in glial cells in structures called
glial fibrilary tangles (GFPs). The most common disease
where NFT’s are found is Alzheimer’s disease (AD).
Aggregated tau also accumulates in progressive supra-
nuclear palsy (PSP), corticobasal degeneration, frontotem-
poral dementia with parkinsonism-chromosome 17 type
(FTDP-17), Pick’s disease (PiD), Down syndrome, post-
encephalitic Parkinsonism, Niemann Pick’s disease, and
numerous other neurodegenerative diseases. NFTs are also
prominent in normal aging, but to a diminished extent
compared to disease states. The aggregated tau found in
these different neurodegenerative diseases is hyperphos-
phorylated relative to tau in non-disease adult brains, and
the disease phosphorylation pattern resembles that found in
fetal brain. This diverse set of sporadic and familial
neurodegenerative disorders is referred to as btauopathiesQ.
2. MAPT mutations and FTDP-17
For most tauopathies, the role of tau aggregation in the
initiation and progression of neurodegenerative disease is
unknown.However,the discovery ofmissense andsplicesite
mutations in subjects with FTDP-17 established that abnor-
mal regulation of the tau gene (MAPT) or abnormal tau
inheritedasan autosomal dominantdisorder andisagroup of
clinically heterogeneous syndromes with overlapping behav-
ioral, cognitive and motor abnormalities [25–27]. At least 34
different mutations in the human tau gene (MAPT) have been
reported (Table 1). These mutations fall into two functional
classes. One class, referred to here as protein function
mutations, affects the function of the tau protein. This
mutation class includes missense and deletion changes in
the coding regionof the gene. The result of these mutations is
a reduction in the affinity of tau binding to MTs and the
consequential reduced ability of mutant tau to induce in vitro
polymerization of MTs. Also, at least some of these protein
function mutations accelerate the in vitro aggregation of tau
to form filaments that resemble those isolated from disease
brains. Protein function mutations in constitutive exons E1
(R5L, R5H), E9 (K257T, I260V, L266V, G272V), E11
(L315L, L315R, S320F), E12 (Q336R, V337M, E342V,
K369I) and E13 (G389R, R406W) are present in all six tau
isoforms [22,23,28–40]. E10 mutations D280K, N296H,
D296N, P301S and P301L affect the biochemical properties
of only 4R forms [30,41–48]. For example, aggregated tau in
P301L patient brain is composed primarily of mutant 4R tau
as detected by site-specific antibodies [49,50].
The second class of mutations alters the alternative
splicing of MAPT transcripts, primarily affecting the
regulation of E10 splicing (Fig. 2). Mutations in this class
include missense (N279K, N296H, S305N), silent (L284L,
N296N, S305S), deletion (D280K, D296N), and intronic
mutations (E10+3, E10+11, E10+12, E10+13, E10+14,
E10+16, E10+19) [23,24,42–46,51–63]. The result of these
mutations is that the 4R/3R isoform ratio is altered (Table 1).
Most of these mutations increase E10 inclusion and raise the
normal 4R/3R ratio from 1 to 2–3 . Mutations D280K
and possibly E10+19, which dramatically decrease E10+
levels in splicing assays, are expected to reduce the E10+/
E10 ratio to 0.33, though autopsy material from subjects
Fig. 1. Genomic structure of the human tau gene; of 14 exons, exons 2, 3 and 10 (white box) are alternatively spliced. Constitutive exons are shown in black.
Six tau isoforms produced in adult brain are shown. Exons 9–12 each encode a MT-binding repeat sequence (grey box). The presence of E10 adds an extra MT-
binding repeat genrating 4R tau 3R tau isoforms lack E10, 4R and 3R tau isoforms is further differentiated at the N-terminus by the conditional presence of
exon 2 (1N) or exons 2 and 3 together (2N). Absence of both exons generates 0N3R and 0N4R isoforms. Amino acid numbers are to the right.
I. D’Souza, G.D. Schellenberg / Biochimica et Biophysica Acta 1739 (2005) 104–115
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