As cells age, the nucleus lets the bad guys in

Stable pore proteins in nuclear membrane stick around but also weaken

As cells get older, they don’t lose their hair or teeth. Instead, they lose control over their nuclear membrane, the protective barrier that encases DNA in the nucleus, concludes a study published in the Jan. 23 Cell. This age-dependent leakiness may be closely tied to cell deterioration and age-related diseases such as Parkinson’s and Alzheimer’s, the new work suggests.

“The implications of this study for our study of brain aging and for neurodegenerative diseases are potentially profound,” comments John Woulfe, a specialist in age-related diseases at the University of Ottawa in Canada. The new findings, he says, represent “an important step forward by bringing the gateway to the nucleus, the nuclear pore, into the fray.”

Nuclear membranes are like screen doors on a porch: They let the refreshing breeze in but keep the mosquitoes out. The double-layered membrane allows nuclear entry for VIP proteins, most of which control gene activity. The proteins travel into the nucleus through channels in the membrane called nuclear pores.

Meanwhile, damaging chemicals and proteins that float around in the cell’s cytoplasm, the jellylike liquid that surrounds the nucleus and other organelles, are rebuffed by the membrane.

Using cells from small worms called Caenorhabditis elegans and cells from rats, Martin Hetzer of the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues found that the proteins that form a nuclear pore stay in the same location for the remainder of the cell’s life. The researchers monitored the location of these pore proteins by marking several of them with green fluorescent protein. After seeing that the pore proteins stay in the same place on the same cells, the researchers concluded that these pores “exhibit extreme stability.”

These nuclear pores are unusually long-lived for cell parts, says Hetzer. Just as drivers replace worn-out parts as cars get older, most cell parts are constantly replaced. But nuclear pores are in it for the long haul. “We think that pores are among the most stable, if not the most stable, structures in our cells,” says Hetzer.

Because nuclear pores don’t get repaired or replaced, Hetzer and colleagues next wanted to know whether the pores maintain a high level of performance even as the cell ages.

The researchers found that old cells’ nuclear membranes allow entry to molecules that are excluded in cells’ younger days. Fluorescently labeled molecules normally too large to enter the nucleus slipped right through old nuclear membranes, while younger nuclear membranes performed perfectly.

Perhaps most dangerous, a protein called tubulin that is usually restricted to the cytoplasm was able to slip through the nuclear membrane of old cells, the researchers saw.

Filamentous tangles of tubulin in the nuclei of cells have been linked to the aging process and to neurodegenerative diseases. These nuclear filaments are known to increase with age, but their origins have been a mystery, says Hetzer. Patients with Parkinson’s disease have such tangles in cells in a brain region known to be affected by the illness. “We speculate that the nuclei in these patients are leaky,” says Hetzer.

The research team’s next step is to study the link between leaky nuclear membranes and age-related diseases. If leaky nuclei contribute to the cellular degeneration seen in neurodegenerative diseases such as Parkinson’s and Alzheimer’s, then leaky nuclei may “represent a viable future therapeutic target,” says Woulfe.

Laura Sanders

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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