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A Comeback for the Ages: Lamin’s connection with aging has reinvigorated research
November 2006--Celebrity can be fleeting. One day you're on top of the world; the next, no one will return your calls. Fortunately, everyone loves a good comeback story, and if there's a scientific equivalent of one, it would have to be the lamins.
Until recently, these once-hot structural proteins dwelled in relative obscurity, but thanks to a connection to progeria — a disease of dramatic, premature aging and possibly to normal aging, lamins are again the toast of the town.
Lamins A, B and C, so named because they make up the nuclear lamina, a mesh-like support structure, were discovered a generation ago. Their robust expression and confinement within the nucleus made the filamentous proteins ideal subjects for fluorescent microscopy and other living-cell studies.
But the work never rose much above fundamental structure-clarifying, says Tom Misteli, a Hopkins collaborator at the National Cancer Institute. It was something like actin when it was first isolated, he says: "novel but unexciting."
Inevitably, without a broader cell biology context or any tie to the human condition, lamins saw their spotlight dim. You really find a dearth of literature for about a decade, says Susan Michaelis, a professor of cell biology.
The comeback began in the 1990s, when lamin defects were found to account for one type of muscular dystrophy. In short order, additional diseases surfaced, including other muscular dystrophies, lipodystrophies, cardiomyopathies and neuropathies. To researchers, great surprise, the mutated lmnA gene (which encodes lamin A and C) produces humankind's largest range of diseases, Misteli says.
But 2003 brought the most unexpected disease connection. Scientists discovered that Hutchinson-Gilford progeria syndrome, the rare and fatal aging disease, could result from an aberrantly spliced lmnA.
Considering the mechanical pressures that muscle cells face, it's easy to see how a flawed structural protein could cause dysfunction. But lamin causing such a wide range of defects, enough to give a 10-year-old the arthritic and cardiovascular conditions of someone aged 70? That was huge.
Researchers returned lamin to the bench. Some, like Kris Dahl, a postdoc in Kathy Wilson's cell biology lab, began asking about the nuclear lamina's mechanical properties. Using a system enabling close study of the cell anatomy, Dahl found that lamins form a tight network of rods that make the nuclear envelope above highly elastic, but not very compressible. In effect, the lamina is a molecular shock absorber.
But subjecting nuclei from healthy and diseased cells to a molecular stress test showed Dahl even more. Interestingly, progeria nuclei don't display the extreme fragility of nuclei that totally lack lmnA; they exhibit the same level of acute stress resistance as healthy cells. However, the lamina in progeria cells cannot rearrange itself correctly following mechanical pressure; therefore, with continued stress it becomes less and less deformable, eventually making the nucleus itself brittle.
Michaelis and her lab have taken a different approach, focusing on the specific changes in lamin A that spark the nuclear abnormalities.
"Lamin A undergoes a series of modifications to generate the mature protein," she says.
Early on, a farnesyl group, a lipid-based hydrocarbon tail, gets added to lamin A's precursor. Ultimately, though, for reasons unknown, the farnesyl and several amino acids are sheared off by a zinc metalloprotease.
In progeria, however, this cleavage doesn't occur because the mutant form of lamin A lacks the cleavage site. So it's the persistently attached farnesyl group, Michaelis says, that causes progeria. She found that truth by showing that farnesyl-transferase inhibitors (FTIs), a class of drugs that inhibit farnesyl attachment, can halt or even reverse progeria's nuclear defects.
The buzz Michaelis' work created increased when Steve Young, a longtime collaborator at UCLA, showed that FTIs could improve bone density and delay disease onset in a mouse model of progeria. Just a few years after lamins were first implicated in the disease, a clinical trial using FTIs for children with progeria was being readied.
"This is a remarkable story of what basic research can accomplish when the community gets fired up," Michaelis says.
And now researchers have set their sights on an even grander stage: a connection between lamins and normal aging. Preliminary findings from Misteli's lab suggest that lamin defects occur during aging. Some in the field, however, question whether that's a response or a cause.
The answer, they say, is their Holy Grail. But even if that connection doesn't pan out, no matter. The lamin story could still be called one of science's smashing comebacks.
Susan Michaelis of Cell Biology on good lamin going bad