‘Intriguing Link’ in Batten Synapse Dysfunction Found in New Study

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Batten disease-causing mutations may lead to dysfunction of synapses, the structures that nerve cells use to connect with each other.

That’s according to data reported in “Transmembrane Batten Disease Proteins Interact With a Shared Network of Vesicle Sorting Proteins, Impacting Their Synaptic Enrichment,” a new study published in Frontiers in Neuroscience.

The researchers say their findings reveal “an intriguing link” between impairments in these synapses that at first glance seem inherently different.

An inherited disorder, Batten is caused by mutations in the CLN family of genes. These mutations are known to cause dysregulation, or impairment, of lysosomes, which are cellular “recycling centers” that help break down complex molecules into simple components for reuse.

Batten disease mainly affects the nervous system, and it has long been assumed that this is because neurons (nerve cells) are particularly sensitive to lysosome dysfunction. However, there is little hard evidence of this, and the molecular mechanisms that cause nervous system problems in Batten remain incompletely understood.

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To learn more, a team of scientists in the U.S. conducted a cellular screen for protein interactions. Specifically, it searched for cellular proteins that physically interacted with three Batten-associated proteins — CLN3, CLN6, and CLN8.

The screen revealed hundreds of proteins that interacted with at least one of the three, and 263 that interacted with all of them. Functional analyses of these shared interacting proteins suggested that many of them were important for the function of synaptic vesicles, a sort of storage container.

A synapse is a place where the long, wire-like projections from two separate neurons meet. When an electric signal is sent down one of the neurons, it triggers the release of signaling molecules called neurotransmitters. These neurotransmitters flow across the synapse and activate receptors on the other neuron, thereby prompting further electrical activity in the recipient neuron. Synaptic vesicles are the “containers” that neurons use to store neurotransmitters until they are ready to be released across the synapse.

In further experiments, the researchers analyzed brain tissue from mice with mutations affecting CLN3, CLN6, or CLN8.

“This revealed striking defects in synaptic composition across all three genotypes,” the team wrote.

The results showed that neurons in these mice had reduced levels of several proteins necessary for vesicle function in the synapses, particularly a set of proteins called the SNARE complex that is important for neurotransmitter release.

The researchers noted that many of these proteins were present at unusually high levels in other parts of neurons. That suggests that Batten-causing mutations could cause dysregulation in how proteins are sorted or trafficked within neurons.

“Collectively, our results … demonstrate novel neuron-specific roles for CLN3, CLN6, and CLN8 in the regulation of synaptic composition,” the scientists wrote, adding that these findings imply that “transmembrane Batten proteins interact with a diverse repertoire of proteins important for cellular trafficking and vesicular sorting.”

Further, the team noted that lysosome function also was dysregulated in the neurons of mice with the three Batten-causing mutations. Those findings are in line with what is already known about the cellular effects of Batten disease.

“The fact that key regulators of vesicle targeting (i.e., SNAREs and tethers) are dysregulated similarly to lysosomal proteins (e.g., vacuolar ATPase subunits), provides an intriguing link between seemingly disparate dysfunctions in synapses and lysosomes. Further work will be required to define the molecular-level causes of these defects and the relative contributions of the various synaptically depleted interacting proteins,” the scientists concluded.