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Susan Michaelis of Cell Biology
on good lamin going bad:
Your lab’s focusing on progeria research, but what, specifically?
MICHAELIS: Right now we’re investigating lamin A processing events, namely, their precise locations in the cell and how they contribute to progeria’s symptoms. What we know is that “healthy” lamin A forms, in part, after a protease cleaves already-modified precursor molecules. In mutated lamin, the sort one sees in progeria, no cleavage occurs. What we don’t know is why that would cause such abnormal nuclei or such severely premature aging. Nor do we know why lamin undergoes modifications in the first place, only to have them cut off.
Have you any idea why an uncleaved farnesyl group might be harmful?
MICHAELIS: Farnesyl, as a lipid group, is important for anchoring proteins in membranes. Normally, lamin A’s farnesyl group gets removed—an event that leaves lamin A adjacent to the nuclear envelope, though not part of it. A current model for progeria suggests that mutated lamin A gets stuck partly in the envelope above and partly in the lamina below. Being in both places at once perhaps causes problems. This is just a hypothesis, though, since we don’t yet understand all the roles farnesyl groups play.
What you’ve found might have some bearing on therapy, yes?
MICHAELIS: Yes. It turns out that another protein that undergoes the same farnesyl- modifying as lamin A is the oncogenic Ras protein. Many years ago people thought that if they interfered with farnesyl processing, they might eliminate cancer-causing, hyperactive Ras. The offshoot was the farnesyl transferase inhibitors—some of our oldest rationally designed drugs. While we don’t conclusively see FTIs as anticancer drugs, the good news is that years of clinical trials show their side effects are mild. And because we’ve found that they can prevent many of progeria’s cell defects, that makes two compelling reasons to explore them as treatment.
Looking ahead, do you think that defective lamins might play a role in natural aging?
MICHAELIS: One way to see how progeria might be relevant to normal aging is to recall that the progeria mutation, a single nucleotide change, dramatically alters the way cells handle and splice lamin A. So you can imagine a scenario in normal cells where the splicing machinery might get sloppy with age, and people accumulate the same altered lamin A as found in progeria. The effects in children with the disease would be similar to those you see in normal aging.