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Cancer protein directs synapse formation, study shows

by  /  21 October 2010

Missed connection: Blocking the cancer protein APC prevents the neat clusters of proteins(above) needed to form functional synapses (top).

A tumor suppressor best known for its role in colorectal cancer plays a crucial role in forming connections between neurons, according to a study published in August in the Journal of Neuroscience1.

The investigators say that the protein, adenomatous polyposis coli (APC), helps direct neuroligins — proteins that are key suspects in autism — to the right place at the connections, or synapses.

Mutations in neuroligin genes have been found in some people with autism2, suggesting that the disorder stems from dysfunctional synapses3.

The new study hints that problems in transporting neuroligin to the receiving end of a synapse may also contribute to autism. When APC or its binding partners are blocked with interfering proteins, clusters of neuroligin don’t assemble correctly, and synapses don’t form properly, researchers show in the new paper.

Geneticists first associated variants in the APC gene with autism in 20074.

Identifying APC as a potential new player in localizing neuroligin is important, but the details still need to be worked out, says Kurt Gottmann, professor of neurophysiology at the University of Düsseldorf in Germany, who was not involved with the work.

In June, Gottmann and colleagues reported that N-cadherin, another adhesion protein — so called because it links cells together — helps direct neuroligin into place5. “I think that the molecular interactions between different adhesion systems will turn out to be rather complex,” he says.

Two sides:

Creating a working synapse involves more than getting an axon, the thin, signal-transmitting finger of a neuron, to contact its target neuron. Specialized sets of machinery must be assembled on both sides for the synapse to operate at full capacity as a mature connection.

For example, on the pre-synaptic side, sacs filled with chemical messengers congregate inside the contacting axon, close to the edge of the cell membrane where they are eventually released. On the post-synaptic side, the receptors receiving these chemical messages cluster together into a tight formation.

APC appears to participate in triggering these events on both sides of the synapse.

“It’s a beautiful system for coordinating the maturation of the pre-synaptic and post-synaptic portions of the synapse, so that you have efficient signaling between neurons,” says lead investigator Michele Jacob, professor of neuroscience at Tufts University.

In 2004, Jacob and her team discovered that APC helps receptors for the neurotransmitter acetylcholine assemble on the post-synaptic side6.

The new study shows that it also plays an indirect role on the pre-synaptic side, by helping neuroligin locate its place on the post-synaptic membrane. Once in place, neuroligins stick out from the post-synaptic side of a neuron to physically interact with neurexin, which is anchored on the tip of the contacting axon. Neurexin has also been implicated in autism. This interaction helps grow the connection on the pre-synaptic side, by clustering the chemical-filled sacs, called synaptic vesicles, into place7.

By directing neuroligin into place, APC could ensure that the synaptic vesicles assemble directly across from the receptors that need to receive the chemicals they release, Jacob says.

Parsing interactions:

Although APC does not bind directly to neuroligin, other proteins link the two together. For example, APC binds to a protein called beta-catenin, which in turn binds with the synaptic cell adhesion molecule, or S-SCAM. S-SCAM then interacts directly with neuroligin. Alternatively, APC binds to a protein called PSD-93, that then binds with neuroligin.

The scientists blocked one of these pathways and left the other unchanged to see whether neuroligin can still form clusters.

They found that interfering with protein binding in the beta-catenin pathway — specifically between beta-catenin and S-SCAM — diminishes S-SCAM levels and disrupts the formation of neuroligin clusters. PSD-93 levels remain unchanged, however, indicating that it cannot direct the formation of neuroligin clusters on its own.

This interference also wreaks havoc on the pre-synaptic side, preventing neurexins and other pre-synaptic proteins from gathering in the right location.

This and other experiments suggest that APC helps direct neuroligin clustering. Still, the experiments stop short of a direct test of APC’s role, Gottmann says.

Jacob is testing a transgenic mouse that lacks APC at glutamate synapses in the brain. The mice show some behaviors reminiscent of autism, including problems with learning and memory, and abnormal social interactions with other mice. “So far it looks like it will model the human disease,” Jacob says.

In people, mutations that completely disable APC lead to familial adenomatous polyposis, a condition marked by an accumulation of polyps in the colon that eventually turn cancerous.

Although that disorder is not linked to autism, a study exploring behavioral aspects of the disease is under way, says Nicholas Davidson, head of gastroenterology at Washington University in St. Louis.

Davidson and his colleagues are interested in whether people with the disorder make lifestyle choices that affect the outcomes of their cancer.

This line of research might turn up subtle cognitive or emotional differences reminiscent of autism compared with people who have other types of cancer. “We have no data at this point, but it seems like an area worth pursuing,” Davidson says.

References:

1. Rosenberg M.M. et al. J. Neurosci. 30, 11073-11085 (2010) PubMed

2. Jamain S. et al. Nat. Genet. 34, 27-29 (2003) PubMed

3. Südhof T.C. Nature 455, 903-911 (2008) PubMed

4. Zhou X.L. et al. Am. J. Med. Genet. B Neuropsychiatr. Genet. 144B, 351-354 (2007) PubMed

5. Stan A. et al. Proc. Natl. Acad. Sci. USA 107, 11116-11121 (2010) PubMed

6. Temburni M.K. et al. J. Neurosci. 24, 6776-6784 (2004) PubMed

7. Wittenmayer N. et al. Proc. Natl. Acad. Sci. USA 106, 13564-13569 (2009) PubMed