Children diagnosed with Hutchinson-Gilford Progeria Syndrome ( HGPS ) race through life against an unfairly fast clock.
Cases are extremely rare: one in 8 million births.
They begin life in apparent good health but by sixeighteen months develop the first signs of premature aging, including hair loss, stiff joints, osteoporosis and atherosclerosis.
Typically, the HGPS race through life runs out by age 13, finished by heart attacks or strokes.
Researchers made a breakthrough in 2003, tracing HGPS to a spontaneous mutation in a gene encoding an important structural component of the cell nucleus.
The inner membrane of the nuclear envelope is lined by tough but adaptable proteins called lamins. The mutated gene for HGPS affected the nuclear lamin A protein.
The discovery that progeria was a " laminopathy," a disorder caused by a nuclear lamin failure, gave HGPS families new hope because it gave clinical researchers new targets for drug or other interventions. But the discovery gave cell biologists a new problem.
If HGPS was cellular aging run wild, was it a warp-speed version of "normal" aging ?
If so, what was it about the mutated lamin A protein behind HGPS that causes cells to age so rapidly ?
In work, presented at the 45th Annual Meeting of the American Society for Cell Biology in San Francisco, Robert Goldman and his collaborators at the Northwestern University's Feinberg School of Medicine and elsewhere describe how they've zeroed in on the defective lamin A proteins linked to HGPS. While lamins polymerize into fibrous structures that hold up the "walls" of the nucleus, they also serve as an internal scaffold for the complex machinery involved in DNA replication and gene expression. It was in this later role that the researchers have been looking for clues to premature and possibly to normal aging.
Reporting on two sets of experiments, Goldman et al say that the mutant lamin A protein seems to interfere with key controls of gene expression and of the cell cycle.
The first study discovered that the most common HGPS-linked mutant lamin A protein alters the organization of regions of chromosomes that are critically important in regulating gene expression. These so-called heterochromatic regions include the inactive X ( Xi ) chromosome found in normal female cells.
One of the hallmarks of Xi heterochromatin is its association with proteins known as methylated histones. In the cells from a female HGPS patient, the researchers found that levels of this molecular hallmark and of an enzyme required for histone methylation of Xi are sharply lower.
The second set of results reveals mutant lamin A proteins turning up in the wrong place -- too tightly linked to the membranes of the nuclear envelope -- to be of much help during key stages of the cell cycle.
The researchers believe that this localization failure of mutated lamin A proteins would severely compromise the ability of HGPS cells to engage in normal DNA replication, a probable factor in their rapid march to premature senescence. Whether similar missteps and miscues by nuclear lamins are part of "normal" human aging is the question that draws researchers onward, says Goldman.
Source: American Society for Cell Biology, 2005