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Leaky cells linked to ageing process

Published 22/01/2009

Leaky cell nuclei that cease to operate efficient checkpoint controls may be an important factor in the ageing process, research suggests.

The cell nucleus is bound by a membrane covered with protein "pore complexes" that act as gatekeepers, selectively allowing the molecular ingredients of life in or out.

Tight security on these entrances to the nucleus, the functional heart of the cell, is essential. But now scientists have discovered that as we age, it gets slacker - potentially leaving cells vulnerable to harmful molecules slipping through the city walls.

Each of the "gates", made up of 30 different proteins, controls an estimated 1,000 passages a second. Movement of molecules in and out of the nucleus is necessary to allow, among other things, the assembly of new proteins according to genetic instructions.

Researchers at the Salk Institute in La Jolla, California, found that some of these pore proteins remain in place without being renewed for the whole of a cell's lifetime.

Over time, they deteriorate and are eventually lost. Like a checkpoint that has been abandoned by its guards, the protein complex then becomes an open door. Laboratory experiments showed that the nuclei of old rat neurons containing damaged pore complexes grow increasingly permeable.

Even if most of the hundreds to thousands of pores on any given cell nucleus are in good shape, damage to a few can make the nuclear membrane leaky.

Dr Martin Hetzer, from Salk's Molecular and Cell Biology Laboratory, said: "We predict that when the permeability barrier is impaired, molecules are either lost from the nucleus or can leak into the nucleus and thereby change gene expression profiles."

His team was able to show that long filaments of a protein called tubulin, normally found only in the cytoplasm, the "body" of the cell, invade nuclei through damaged pores.

Experts have been aware of these filaments for 100 years, but their origins were previously unknown. The filaments are associated with several neurodegenerative diseases, including Parkinson's.

"This could be a general ageing mechanism, and it provides an explanation for the origin of these filaments, which have been known by pathologists for a long time," said Dr Hetzer.

Finding ways to prevent or reverse the leakage of cell nuclei could open the door to new treatments for diseases of old age, said the scientists reporting their findings in the journal Cell.

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