The role of the microtubule-associated protein tau in neurodegenerative disease.
One bullet with many triggers. The tau protein is
a microtubule-associated protein that plays a role in stabilizing neuronal microtubules.
In addition, it is incorporated into filamentous lesions in a number of
neurodegenerative diseases known collectively as
tauopathy is the most common of which is Alzheimer's disease,
which is the major cause of dementia in the elderly.
In this presentation, I'll describe genetic findings over
the past 10 years that have established
the mechanistic importance of power in neurodegenerative disease.
Then, in the second part of the talk,
I'll describe more recent efforts to generate
transgenic mouse models of these diseases by
expressing tau transgenes in transgenic animals.
The microtubule-associated protein tau is encoded by
a single gene on chromosome 17 have because it's one,
two, three, and ten are alternatively spliced.
There are six major protein isoforms in the adult human brain.
Exons 9 through 12 encode the microtubule-binding domains within the tower protein.
These are imperfect repeats of 31 and 32 amino acids and
because exon 10 is alternately spliced,
we actually have two major groups of isoforms that contain
three microtubule-binding repeats when exon 10 is spliced out
or four microtubule-binding repeats when exon 10 is spliced in.
These are known usually as three repeat and four repeat tau.
The average isoform ratio of three repeat to four repeat in the normal,
human adult brain is around one to one.
However, it's important to point out that in the fetal brain,
we only see the shortest three repeat isoform and in addition,
in patients with certain types of tau mutation,
they're associated with frontotemporal dementia.
We see a shift in the 3-4 repeat ratio such
that there is a large increase in the level of four repeats to isoforms.
The normal function of the tau protein is to