Sci. Aging Knowl. Environ., 21 January 2004
Protein unexpectedly spurs brain cells to branch
After enough beers, even the shyest bar patrons will tell their life stories to complete strangers. Brain cells also need chemical help to make connections. A new study reveals that an unlikely protein prompts brain cells to sprout extensions, a key step in making memories. The work could help researchers understand how neurons network and why these branches shrivel in some diseases.
Numerous studies suggest that the growth of dendrites, antenna-like extensions that link brain cells, helps solidify memory and learning. For example, putting rats in a cage with many objects to explore increases the number of dendrites in certain parts of the brain. In illnesses such as Alzheimer's disease, the number of branches declines in the hippocampus, a brain region crucial for laying down memories. What controls branching is uncertain, but some evidence points to the compound guanine and its relatives. For example, several researchers have found that enzymes activated by a derivative of guanine called GTP spur dendrites to sprout and lengthen. And in 1999, neuroscientist Bonnie Firestein of Rutgers University in Piscataway, New Jersey, and colleagues noticed that a protein called cypin, which chops a piece off of guanine, seems to increase dendrite numbers. The work hinted that cypin increases dendrite numbers.
To investigate cypin's influence on branching, the researchers hiked production of the protein by inserting an extra copy of its gene into brain cells in culture. The alteration boosted the number of dendrites. Using a new technique that stymies messenger RNA formation, the team then reduced cypin output, which trimmed the number of dendrites on brain cells. These results establish cypin's role in branch formation.
Cypin has three regions, each of which performs a different job. To find out which one sparks dendrites to grow, the team slipped DNA fragments that code for different parts of the protein into the cells. Only the snippet that encodes the guanine-slicing section promoted branching, which could mean that this reaction helps induce outgrowths. Additional experiments suggest how. To produce new dendrites, the cell must construct microtubules--protein struts, built from multiple copies of a protein called tubulin, that act as a cellular skeleton. Mixing cypin with tubulin in the test tube yielded microtubules, the team found. The results suggest that cypin instigates branching by prodding microtubules to form, says Firestein. Because cypin elicits branching only if it contains the guanine-cutting region, the mechanism might involve this compound. GTP prompts microtubules to assemble, but the team's experiments suggest that cypin does not act through this molecule. The work raises the possibility that stimulating cypin might help maintain dendrites in Alzheimer's disease or other memory-stealing conditions, says Firestein.
The result is surprising, says neuroscientist Fen-Biao Gao of the University of California, San Francisco, because researchers have thought of cypin as a "housekeeping" protein that governs concentrations of guanine, rather than one that alters dendrites. The next step, he says, is to "figure out how a metabolic enzyme can regulate microtubule dynamics, which is key for dendrite growth." Further work might reveal what prompts neurons to reach out and make new ties.
January 21, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150