A new paper by Firestein and her colleagues at Rutgers, The State University of New Jersey, examines the role of the protein snapin in nerve branch, or dendrite, patterning and its potential as a drug target in therapies aimed at learning and memory disorders. The article will appear in the journal Molecular Biology of the Cell but appeared online today at MBC in Press (www.molbiolcell.org/in_press.shtml).
While disorders like autism may arise from a multiplicity of causes, research at the cellular level, such as that of Firestein and her Rutgers team, is creating an important point of entry for early intervention with therapeutic drugs.
Dendrites are the input centers of neurons -- where nerve cells receive information that they pass on to another nerve cell or to the brain. When there is an abnormal decrease in dendrite branches, there are fewer sites to receive information and communication may be impeded. Individuals with disorders such as autism and Rett syndrome display not only fewer branches, but also show two quite different dendrite patterns. Firestein's most recent work explores the how and why of dendrite branching and patterning.
"It's not just how many branches there are, but where they are and the pattern they form," said Firestein, an assistant professor in Rutgers' department of cell biology and neuroscience. "The patterning actually affects the way a cell signals and understanding the patterning could be just as important as understanding how many branches are there. Ultimately, this could lead to new drugs designed to modulate the patterning activity."
Firestein has worked extensively with cypin, a protein that regulates dendrite numbers (a news release is posted online at ur.rutgers.edu/medrel/viewArticle.html?ArticleID=3708). Cypin works on tubulin, a protein that is a structural building block of the dendrite skeleton. Now Firestein's research group has turned its attention to the protein snapin. When snapin binds to cypin, tubulin is crowded out, so fewer dendrites assemble and more branching occurs.
When researchers overexpressed snapin in hippocampal neurons in the lab, the number of primary dendrites growing out of the cell body decreased, but many more secondary dendrites branched off them.
"This is significant not just in identifying snapin as a protein that shapes the dendrites, but also in pinpointing a drug target where one can regulate the interaction of snapin with cypin," Firestein explained.
Both of these proteins have many other functions in the nerve cell environment and elsewhere in the body. "We need to change cypin's function for branching but not its other functions," Firestein said. "Rather than a drug that blocks cypin, we need a drug that affects the binding between the cypin and snapin. This is easier to design and cypin can still function with the other proteins it binds to."
Firestein's goal is to build "a core pathway of dendric branching" – a sequence of steps, each affecting the next, with cypin at the center. "Our pathway says cypin does this; now what regulates cypin? Here snapin has a role. And what does snapin regulate?" said Firestein. "Our hope is in ten years, we will have a whole pathway mapped out so that we can target different points in the pathway with new drugs."
Molecular Biology of the Cell