Protein duo maintains communication among nerves

Frustration gave way to satisfaction when an experiment that seemed to foil St. Jude researchers actually brought them a step closer to understanding how the brain maintains healthy lines of communications among its nerves.

The researchers, headed by James Morgan, PhD, Developmental Neurobiology chair, were studying how the cerebellum - the lower, back part of the brain - maintains the structure and function of synapses. Synapses are the intimate connections between nerves that allow them to communicate with each other. Morgan had previously discovered that proteins called synaptrophins maintain countless millions of synapses in good working order.

In the current study, the St. Jude team focused on two synaptotrophins in the cerebellum, Cbln1 and Cbln3. The researchers found that nerves called granule cells secrete Cbln1 and Cbln3 bound together as a single unit. This pair of proteins then crosses over the synapse to its target nerves - the Purkinje cells.

Previously, Morgan's lab showed that mice lacking the genes for Cbln1 had abnormal connections between granule cells and Purkinje cells and were unsteady on their feet. Since Cbln1 and Cbln3 were always secreted as a team, the researchers thought that eliminating Cbln3 in mice would be just as damaging as eliminating Cbln1. But in the current study, eliminating Cbln3 had no apparent affect - much to the surprise of Dashi Bao, a former postdoctoral fellow who did much of this work.

So Bao went back into the lab and discovered that the combination of Cbln1/Cbln3 ensures that Cbln3 does not get destroyed. Specifically, when Cbln1 binds to Cbln3 it masks one of the building blocks on Cbln3 that would otherwise act as a red flag to signal the cell to destroy it. But in the process, Cbln1 itself is destroyed. That explained why the mice lacking Cbln1 also had no Cbln3. And it explained why mice that lacked only Cbln3 not only appeared normal, they also had a greatly increased amount of Cbln1 than normal, since Cbln1 didn't have to sacrifice itself to save its partner.

"Cbln1 performs a molecular suicide mission in the cell," Bao said. "It normally binds to Cbln3 to rescue it from degradation, but in the process Cbln1 itself is largely destroyed."

One of the questions that Morgan's lab is now trying to answer is, "If mice lacking Cbln1 aren't any worse off if they lack Cbln3 too, then does Cbln3 have a job other than controlling levels of Cbln1?" Such studies could lead to better treatment for neurological and psychiatric disorders caused by faulty communication among nerves.

A report on this work appeared in the December 2006 issue of Molecular and Cellular Biology. Other St. Jude authors of this paper include Leyi Li, PhD, Jennifer Parris and Yongqi Rong, MD, all of Developmental Neurobiology; and former St. Jude employees Marc Morgan and Zhen Pang.