00:00
All right, so an example of a disease having to do with a nuclear membrane.
00:04
This is a tragic disease. It is not a public health menace.
00:07
This is one that is extremely rare, but it's a very illustrative disease.
00:11
And this is called Hutchinson-Gilford progeria.
00:14
So, progeria is a number of syndromes, and Hutchinson-Gilford just happens to be one of them,
but a number of syndromes that lead to premature aging.
00:23
The little kid that -- the little kid in front of you has a body
that's essentially like a 50 or 60-year-old body in terms of its atherosclerotic burden
in terms of the kind of aging and senescence of a number of the tissues including the skin.
00:38
So, they lose their hair. They have a very abnormal joint structure.
00:43
They lose a lot of adipose tissue. So, it's premature aging that happens.
00:48
And it happens because of a mutation of a protein that is part of the normal nuclear membrane.
00:55
So, lamin A is a protein that normally is synthesized and then modified,
so that it can insert into the membrane via a farnesyl linkage.
01:05
Farnesyl is just a lipid linkage.
01:08
And so, it's one of the other ways that proteins can associate with a membrane.
01:11
Normally, in you and I, because we don't have Hutchinson-Gilford progeria,
in us, our protein is such that we can cleave that farnesyl linkage.
01:25
The protein doesn't have a mutation.
01:26
In these kids, they can't cleave it, so that lamin A
stays stuck to the membrane forever and ever.
01:34
And that lamin A anchors additional proteins.
01:37
So, you can see in the upper right-hand side in the circles
are the lamin A nuclear complexes stuck in the nuclear membrane,
and they're associated with a lot of the other purple bars
which represent nuclear cytoskeletal elements.
01:52
So, the lamin A is permanently attached.
01:55
It cannot detach, we cannot cleave it. You and I, we cleave it.
01:59
That leads to an unstable nuclear envelope
that gets pulled by all of those cytoskeletal elements inappropriately.
02:06
And when there's abnormal nuclear shape, instead of being a round or oval structure,
it's indented. It's contorted. It's bizarre-looking.
02:15
And when that happens, we pull the chromatin open by mechanical forces.
02:20
So, we go from heterochromatin to euchromatin,
and we get abnormal transcription because of this defect of a lamin protein,
and it's just one amino acid.
02:30
So, it's abnormal nuclear shape and chromatin organization.
02:34
And this just gives you an example.
02:36
This is just an immunofluorescence study looking at the nucleus
and the nuclear membrane in a normal cell on the left and that contorted,
distorted nuclear envelope that happens in a lamin A mutation
in a patient with Hutchinson-Gilford progeria.
02:53
And you get abnormal transcription which leads to the premature senescence of cells,
which leads to the phenotype that we saw on the previous slide.