January 23, 2009
Leaky Membranes Another Sign Of Old Age
As parts of us age, even the membrane bound nuclei, which house the genetic instructions for life that are "written" in our DNA, begin to show considerable wear and tear, suggests a new report in the January 23rd issue of the journal Cell, a Cell Press publication. The nuclear pore complexes that normally act as gatekeepers--selectively importing and exporting the molecular ingredients for life to and from the nucleus--begin to break down and spring leaks.
That's because some of the 30 or so nucleoporin proteins that make up those complexes can't be replaced once cells stop dividing, they found."These proteins are unusually stable," said Martin Hetzer of the Salk Institute for Biological Studies. "Most proteins turnover within minutes or hours. These last the entire life span of the cell," a period that can in some cases be decades. In fact, he said, many cells in the body do not actively divide most of the time, and that lack of cell division is particularly dramatic for cells such as muscle and neurons.
Earlier studies had shown that some components of the nuclear pore complexes are very dynamic while others hang around throughout the cell cycle, getting replaced only when cells split into two daughter cells, Hetzer explained. His team wondered what that meant for cells that had stopped dividing.
They now report that the scaffold nucleoporins are extremely stable and do not exchange once they are incorporated into the nuclear membrane, persisting for the entire life span of a differentiated cell. In those cells, the nuclear pore complexes deteriorate with time, eventually losing nucleoporins that are critical for maintaining the pore diffusion barrier. Strikingly, they found that nuclei of old rat neurons containing deteriorated nuclear pore complexes become increasingly permeable.
Cells are usually very efficient at getting rid of old or damaged proteins and replacing them with new copies, Hetzer said, but it seems they have no way to replace the most stable components of the nuclear pore complexes. He suspects that's because the pores are not only essential for molecular transport, but they are also structural components of the double lipid layer that is the nuclear membrane. If those gated holes are lost, the membrane collapses, he said.
"How do you replace a bridge while transport is happening?" he asked. "It's not possible."
Even if most of the 100s to 1000s of pores on any given cell nucleus are in decent shape and functioning, damage to a few can turn the nuclear membrane into a permeable barrier, allowing leakage of the wrong molecules in or out of the nucleus. This process might explain a phenomenon first described more than 100 years ago: that the nuclei of brain and other tissues can sometimes accumulate filaments with age. Those filaments often tend to show up in Parkinson's and other neurodegenerative disorders, Hetzer said.
His team now reports that tubulin, proteins that make up the microtubule filaments normally found only out in the cytoplasm, accumulate in nuclei with such leaky pores. That discovery raises the intriguing possibility that defective pores may be involved in the development of human diseases, the researchers said, a notion they intend to explore by examining healthy and diseased human brain tissue.
"Our finding that nuclear 'leakiness' is dramatically accelerated during aging and that a subset of nucleoporins is oxidatively damaged in old cells suggests that the accumulation of damage at the nuclear pore complex might be a crucial aging event," Hetzer's team concludes.
Once they have a better understanding of what happens to those pores in normal aging and neurodegenerative disease, perhaps there may be some way to fix the problem, he said. For instance, if certain proteins tend to be the ones that "go," they might be replaced in some way. Alternatively, if they can determine what it is that goes awry after those pores begin to leak, there may be ways to intervene at the secondary level as well.
The researchers include Maximiliano A. D'Angelo, Marcela Raices, Siler H. Panowski, and Martin W. Hetzer, at the Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, La Jolla, CA.
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