00:01
When you acquire a misfolded protein, the
agent first accumulates in the lymphoreticular
and secretory organs, and eventually spreads
to the central nervous system. And in the
central nervous system, the pathology includes
death of astrocytes, astrocytosis, vacuolization,
the holes in the central nervous system, the
brain that makes it be called spongiform TSE,
that's the 'S' in TSE. And you eventually
lose neurons, slowly but surely neurons go,
and you lose many of your functions. You have
cerebellar ataxia. What does that mean? You
can't walk, you have more and more trouble
walking, until at one point you can no longer
walk. You tend to have dementia, you go crazy,
you don’t recognize people, you start to
just stare and you stop talking, akinetic
mutism, you simply stare straight ahead without
saying a word. There are other issues too,
you can have psychological problems, you can
yell and scream at people for no reason, depends
on which TSE you are getting. And then in
any time from months to years, it can be a
year or it can be 20 years of incubation,
you die. As I said, these are uniformly fatal,
no way to prevent the death. So pretty scary
and a bit insidious. They come from nowhere.
There's no inflammatory antibody or cellular
response to this protein. It's a normal cell
protein. It's just misfolded and our immune
system does not recognize it as different,
so you don't make any antibody response, so
there is no way that you yourself can prevent
this disease from happening. Only if we can
somehow give you some drugs one day, which
we don't yet have.
01:42
Alright, I’m going to tell you about one test for
TSEs that was developed a long time ago, which
for many years was the only way you can tell
postmortem, whether someone had a TSE. And
I said postmortem because you need a little
brain tissue in order to do this, and when
someone presents their doctor with early symptoms
of a TSE, there are in no shape to have a
brain biopsy, so this is done after they die.
The observation was that PrPc, the normal
protein, we see it in its structure on the
right, on the left is a stretched out version
of the protein. If you take say a brain extract
from someone who died of a TSE and you digest
it with an enzyme that digests proteins called
proteinase K. That enzyme will completely
digest this protein away into bits, and if
you run a western blot, which is a way to
detect PrPc specifically with an antibody,
you won’t see anything because it's digested
away. If you take the PrPsc version, which
now has lots of beta sheets and you do the
same thing, you digest it with proteinase
K, that is largely resistant to digestion.
02:53
You clip off a little bit at the left end
of the protein, the end terminus, but pretty
much the protein is resistant to proteinase
K digestion. So right away this is a nice
way to distinguish the normal protein from
the pathogenic protein. And you could take
a sample from a person and subject it to this
assay. If all the PrP is digested, they don’t
have a TSE, but if it's resistant, they do
have a TSE. And you may ask, what does it matter
after they die? Well you want to know what
people died of, and you want to make sure
they're not going to contaminate someone else.
So for example very recently, someone showed
up at an emergency room, they had shot themself
in the head, an attempted suicide, and only
after few hours did they find out that this
person had a TSE, he was going to die, so
they decided to take their life, but in the
meantime he contaminated all the emergency
room with brain material and if they didn't
realize he had a TSE, which they figured out
by a diagnostic test, lots of other people
could've acquired it as well.