Can a cellular traffic jam ‘jam up’ learning?

Image Credit: China Daily/Reuters

By Andy Gao

Having a child is a joyous event for most families, but what if your precious bundle of joy didn’t develop like all of the other children? Imagine scrolling anxiously through parenting books and wondering why your baby isn’t developing the ability to walk and talk normally; why they don’t look like your friends’ babies; and why they might even start convulsing and seizing. Imagine bringing your child to your pediatrician, who conducts a number of examinations but ultimately cannot determine what exactly is wrong with them or how to treat them. What would you do?

This scenario might be hard to fathom, but unfortunately, these are the types of complications that a number of families must face when raising a child with a rare disorder. True to their name, each rare disorder affects only a small number of people, but taken together, they afflict a much more significant proportion of the population worldwide. In fact, since both primary caretakers and the general public may simply be unaware of these disorders, they can often go unnoticed and rates of these diseases may be highly underestimated.

Even so, what if some of the basic cellular deficits underlying some of these disorders could be common to much broader range of more common diseases that people are actually familiar with, such as Alzheimer’s and Parkinson’s? Now, researchers may have discovered one such possible mechanism worthy of further investigation.

Like cities, neurons (brain cells) also need to traffic cargo around them in order to function properly. In order to do this, most cells use small circular structures called endosomes to transport different proteins inside of them. The internal acidity, or pH, of these endosomes is essential for their proper function and is regulated by transporters that pump in or remove hydrogen ions (protons) from these structures. One of these transporters, dubbed NHE6 (or sodium/proton exchanger 6, and if you’re wondering where the N and H come from, look back at your periodic table abbreviations), has gained particular interest in recent years. In particular, the gene encoding NHE6 is found to be mutated in some rare developmental disorders whose symptoms include intellectual disability, movement disorders, severe seizures, autistic behaviour, and more. As NHE6 is involved in cell trafficking, if it isn’t functioning properly, it could result in a cellular “traffic jam” of sorts that could go on to disrupt the function of the entire cell as well. The question then becomes how this cellular “traffic jam” could impair brain function to cause these devastating symptoms.

For a long time, it was known that NHE6 is present in other bodily tissues, including the brain, heart, and muscles, but its role in neural function remained elusive. Recently, our lab characterized the presence of NHE6 in the hippocampus, a brain structure involved in learning and memory. In the neurons of the hippocampus, we found that NHE6 was present specifically at synapses, the points of contact between brain cells that allow them to communicate with one another. Interestingly enough, when we induced a cellular learning model on these hippocampal cells, which usually results in the strengthening of these synapses, we found that more NHE6 was localized to these synapses. These experiments told us that NHE6 was indeed involved in learning and memory in the brain.

We then moved on to address the question of how removing the function of NHE6 could result in the severe neurological deficits that have been observed in rare disorders. To address this, we grew hippocampal neurons in a dish and made them express mutant versions of the NHE6 protein. We found that compared to normal cells, these neurons looked “sick” and didn’t form as many synapses with one another. In addition, they were also less able to transport certain proteins using their endosomes. Interestingly enough, when we induced a cellular learning paradigm, these cells failed to strengthen their synapses like normal cells did. This finding was important, as it could be the underlying mechanism behind cognitive impairment in patients with rare mutations in the NHE6 gene as well as those with more common neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Genome studies in these latter groups of patients have actually uncovered a decrease in the amount of NHE6 in their brains. As a result, this could prevent their brain cells from functioning properly and lead to the distinctive impairments associated with these devastating diseases.

In summary, recent findings have indicated that changes in the functionality of something like NHE6 can indeed impair the ability of brain cells to communicate with one another and, more importantly, strengthen these connections in response to cellular activity. This could, in turn, prevent patients with changes in NHE6 function to learn things about the world around them and form new memories. We hope that by discovering the underlying cause behind such disorders, no matter how rare or common, we can begin to develop new therapeutic measures to manipulate these transporters and reverse the neuronal impairments brought about by cellular mistrafficking.

And even if such therapies are still a long way in the making, at least the families and caretakers of children with these rare disorders know that someone, somewhere, cares about them enough to try and help them with research such as this!

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