Resulting Condition: Hutchinson-Gilford Progeria

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.