00:01
Hello and welcome to Prions. We are going
to be diving a little deeper into this topic.
00:07
And after you've listened to this video, I
hope you'll understand two assays for detecting
prions. You'll know why Mad Cow Disease and
Chronic Wasting Disease may be a threat to
the food chain for humans. You’ll comprehend
the species barrier to prion infections, and
you'll be able to trace the possible origin
of prion diseases.
00:36
Prions cause diseases that we call transmissible
spongiform encephalopathies, which I'll now
refer to as TSEs, and here are some of the
human TSEs: Creutzfeldt-Jacob disease (CJD),
Fatal Familial Insomnia (FFI), Gerstmann Straussler
syndrome (GSS), Kuru, and variant CJD (vCJD).
01:02
These are human TSEs, they are also TSEs of
animals.
01:07
TSEs or prion diseases are protein misfolding
diseases. They involve the misfolding of a
normal cell protein. So let's explore exactly
what that means. The normal cell protein involved
in TSEs is called the prion protein PrP with
the superscript C, which means it's the cellular
version. And shown here on the left is the
structure of the PrPc protein. It's the normal
version. You can see lots of swirls in this
protein, those are alpha helices. This protein
has high alpha helical content and very low
beta sheet content. The pathogenic version
of PRP, which is associated with TSEs as shown
on the right, is called PrPsc, SC stands for
scrapie, because that was the first TSE discovered,
and the one where the role of the prion protein
was figured it out. This protein is abnormally
folded. Now we don't have the structure of
this solved, but we think it has a lot of
beta sheets and you can see those four long
sheets going up and down in green and in yellow,
those are beta sheets. So this is a conformational
alteration of the normal protein. We have
the normal protein and a conformationally
altered PrPsc, and that PrPsc is pathogenic,
when you accumulate that in your brain, you
develop a TSE. It’s a very unusual disease.
So pathogenic prion, PrPsc, is a conformational
isoform of a normal host protein PrPc. Prion,
the word prion stands for proteinaceous
infectious particle, and you might hear me
say “prion” or “prion”. I really don't
know what's right, when you have a word invented
by people, what's the difference on how you
pronounce it? As long as you say “prion”
or “prion”.
03:14
Prions are normal proteins on the outer surface
of neurons. They are found in a few other
places, but mainly on the outer surface of
neurons. As in this slide, you can see at the
bottom, a lovely neuron with the cell body,
and then the axons and dendrites, and there
on the surface is the normal cell, prion protein
PrPc. So it has functions on the outside
of a neuron, it is GPI linked. So it is not
a transmembrane protein, but it is linked
by a chemical linkage. When you acquire the
pathogenic form of prion, PrPsc, let's say
you ingest some meat that has bovine prions
in it, bovine pathogenic prions. You'll eat
that beef, it will go into your intestines,
and shown here on this side, is a layer of
mucosal cells, and on one of those mucosal
cells, there are some normal PrPc, and you
should be able to tell me which one it is,
because you know it doesn't have a lot of
beta sheets, alright. And then coming in just
to the left of it, is a little bit of the
abnormal protein PrPsc. It has beta sheets.
You've just eaten this, so that's coming into
your intestines. What we think happens, it
comes in and causes the normal protein to
convert to the abnormal form. It causes it
to convert. This is really incredible.
04:39
The abnormal protein finds a normal version of
the protein and it makes it fold, like it
is folded, from PrPc into PrPsc. So that’s
shown here, the pathogenic protein is next
to the normal protein, and then the normal
protein is now converted into a pathogenic
one. It now has a lot of beta sheet structure.
You can see those two proteins are now PrPsc.
05:02
And the idea is, this happens in the intestine,
you then ingest, you then take up those proteins
and they travel via various pathways, to neurons
in your central nervous system and there they
convert additional PrPc to PrPsc and when
you have enough or more PrPsc, then you start
to develop the symptoms of a TSE. And eventually
you die, you will always die when you start
to develop a TSE. We don’t yet have any
way to stop it. Fortunately these are very
rare.
05:37
So there are three ways that you can acquire
or develop a TSE, also known as a spongiform
encephalopathy, because of the spongy appearance
of the brain when it accumulates a lot of
these PrPsc proteins. So again on the left
we have our normal protein PrPc, on the right,
the abnormal PrPsc. There are three ways to
get from normal to abnormal. You can acquire
some PrPsc, you can eat it in beef or it can
be introduced into you by a corneal transplant,
if you get a cornea from someone who has PrPsc,
maybe they don't know about it at the time when
they die and donate the cornea, you can acquire
PrPsc. You can get it from human hormones
or other blood products. There are ways to
get it. So this is the infectious form. You
get that PrPsc and it converts your PrPc into
more PrPsc and you develop the disease.
06:36
A second way you can acquire this is by genetics.
The luck of the draw. You get a mutation from
your parents in the prpn gene, the gene encoding
PrPc. Single amino acid changes enough to,
at some point in your life make PrPc, start
to misfold, and once there's one PrPsc somewhere
in you, it then makes all your others misfold.
So it’s a genetic disease. So far we’ve
got an infectious disease, we have a genetic
disease, and finally there is what's called
a spontaneous disease, where you don't eat
any contaminated beef, you don't get a corneal
transplant, you don't have a genetic mutation
that predisposes you to misfolding, but for
some reason at some point, one day some of
your PrPc misfolds and becomes PrPsc and you
go on to develop a TSE. Alright, three ways that you
can get this, in the end they are all fatal.
07:32
They all can be transmitted.
07:35
So here is a graph showing you the number
of cases of Creutzfeldt-Jakob disease deaths
in the United States from like 1979 to 2011.
You have deaths in the bars and the death
rate is in green. So what you can see is that
the rate is low, it's 150 to 200, and now
maybe 400 per million population. It's rare
but not unheard of, people die of this regularly.
08:05
And the incidence, this is Creutzfeldt-Jakob,
a certain kind of human TSE, incidence
is slowly rising with time. We don’t know
why this is the case, but it's puzzling and
the more people with Creutzfeldt-Jakob, the
more people are likely to get it, because
they can transmit it to them. So this is a
combination of mostly sporadic or spontaneous
TSEs and genetic. Mostly spontaneous, very,
very little from eating contaminated material.
08:36
Nevertheless it's a substantial burden and
it causes a 100% fatality, you never can recover
from this. Hopefully one day we’ll have
drugs or some way of reversing it, but we
don't at the moment.