Updated 27 July 2009
by Jennifer Kwon, MD., Washington University, St. Louis, with updates
by Michael Hutton and Eckhard Mandelkow
View Tau Mutation Table
View Tau Polymorphism Table
Axonal Transport Dysfunction
Tau is a microtubule-associated protein that is involved in microtubule assembly
and stabilization. In adult human brain, six tau isoforms are produced from a single
gene by alternative mRNA splicing. They differ from each other by the presence or
absence of 29- or 58- amino-acid inserts located in the amino-terminal half and
31-amino acid repeat located in the carboxy-terminal half. Inclusion of the latter,
which is encoded by exon 10 of the tau gene, gives rise to the three tau isoforms
which each have 4 repeats. In the normal cerebral cortex, there is a slight preponderance
of 3 repeat over 4 repeat tau isoforms. These repeats and some adjoining sequences
consititute the microtubule-binding domain of tau (Goedert, et al., 1998).
One of the pathologic hallmarks of Alzheimer's disease (AD) are neurofibrillary
tangles, intraneuronal deposits of paired helical filaments (and fewer straight
filaments) made of hyperphosphorylated tau. Abnormal deposition of tau is also seen
in a variety of other neurodegenerative disorders including progressive supranuclear
palsy (PSP), corticobasal ganglionic degeneration (CBD), and frontotemporal dementias.
Variability in the tau gene has been shown to be a risk factor for PSP (Conrad,
et al.). Recent studies have shown that mutations in the coding and non-coding
regions of tau are directly associated with the development of familial frontotemporal
Forms of FTD have been variously referred to in the literature as disinhibition-
dementia- parkinsonism- amyotrophy complex (DDPAC), hereditary frontotemporal dementia
(HFTD), multiple system tauopathy dementia (MSTD), and pallidopontonigral dementia
(PPND), the syndrome name depending in part on particular prominent clinical and/or
pathologic findings. The various forms of FTD generally share in common insidious
onset of behavior or personality change and dementia typically in the fifth decade,
with other motor findings (Foster,
et al.). Duration is quite variable. The prominent clinical findings in
those affected include: impaired social conduct, diminished speech progressing to
muteness, progressive dementia notable for disturbed executive function and parkinsonian
Pathologically, frontotemporal atrophy is a consistent finding which may be accompanied
by basal ganglia atrophy and substantia nigra depigmentation. Many families have
tau positive inclusions either in neurons or in neurons and glia. And where linkage
data was available, familial forms of FTD were linked to chromosome 17. A consensus
conference decided that the term FTD with parkinsonism linked to chromosome 17 (FTDP-17)
was preferred as it stressed the common clinical and pathologic features shared
by this autosomal dominant, neurodegenerative condition (Foster,
In 1998, a series of papers reported that mutations in tau were associated with
FTDP-17 (Hutton, et
al.; Poorkaj, et
et al., 1997). Since then, other mutations have been described and
are outlined in the accompanying table.
The mutations causing various forms of FTD are of two major types (Goedert, et al.,
1998), coding mutations and intronic mutations. Most coding mutations occur in the
microtubule binding repeat region or very close to it. These potentially lead to
a partial loss of function of tau with reduced tau binding to microtubules (Hong,
et al.; Dayanandan,
et al.; Hasegawa,
et al., 1998; Goedert, et al., 1998;
Spillantini and Goedert). There is also convincing evidence
that tau missense mutations directly increase the tendency of tau to aggregate into
et al., and Goedert,
et al.). Some missense mutations (G272V in exon 9, V337M in exon 12
and R406W in exon 13) affect all isoforms produced, while P301L only alters those
isoforms with 4 repeats. The intronic mutations are all near the splice donor site
of the intron following exon 10. By presumably destabilizing a predicted RNA stem-loop,
there is a change in the ratio of 3-repeat to 4-repeat isoforms (Hutton,
et al.; Spillantini,
Murrell, et al.). There are two coding mutations, N279K and S305N which
appear to enhance splicing of exon 10 rather than to reduce microtubule assembly
(D'Souza, et al.;
Hasegawa, et al., 1999).
Yet it remains unclear how an increase in tau 4-repeat isoforms leads to frontotemporal
dementia. Conversely, the delK280 mutation reduces splicing (D'Souza,
et al.). Again, the significance of this reduction is unclear.
Although the various mutations in tau are associated with frontotemporal dementia,
there are distinctive clinical and pathologic features which seem to be found with
particular mutations. These are briefly summarized in the
Tau Mutations Table. It is clear that the variable tau isoform content in
FTDP-17 tangles is largely explained by the nature of the mutations: Mutations in
or near exon 10 result in tangles consisting predominantly of 4-repeat tau, while
mutations outside exon 10 are associated with tangles with both 4-repeat and 3-repeat
tau. These latter tangles seem to result in filament morphology that is very similar
to that seen in Alzheimer's disease. The filament morphology of 4-repeat tangles
is more variable but generally they have a longer periodicity than the PHFs seen
in AD. Mutations in exon 10 do give glial inclusions and those outside exon 10 generally
do not (but there is at least one exception in press).
Improvements in assays of the functional effects of the tau mutations may enable
us to link the size of these effects to the severity of the clinical phenotype.
It already seems likely that a large effect on micortubule-binding and tau aggregation
equates to a more severe phenotype. In addition, the exon 10 splice site mutations
appear to correlate with clinical phenotype based on the degree to which they disrupt
splicing (thus the +16 mutation appears to be the mildest with incomplete penetrance
while the +3 and +14 are most severe).
We would like to thank Michael Hutton for his advice in the preparation of this page.
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