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SC is caused by mutations in the SLC9A6 gene, which provides instructions for making a protein called sodium/hydrogen exchanger 6 (NHE6). The NHE6 protein is found in the membrane of cell compartments called endosomes, which transport proteins and other cellular materials around cells, helping them decide whether to recycle these materials or discard them into another cellular compartment called the lysosome.

“Endosomes are like little transit vehicles, carrying proteins and other cargo around the cell,” Morrow said.

Endosomes can fuse with a cell’s plasma membrane and expel their contents, a process known as exocytosis, or they can break down and shed cargo. In preparation for the elimination of their contents, the endosome matures and eventually fuses with the lysosome, a membrane-bound organelle with an acidic internal compartment involved in the management of cellular waste.

People with CS lack the NHE6 protein, Morrow said. Previous research published by his team has shown that this lack of NHE6 protein means that the endosome compartment can become more acidic. A major scientific question, in the lab of Morrow and others, has been what happens to the cell when the cargo is too acidified.

For the new study, the researchers used a microscopic marker to highlight and monitor activity in and around the brain cells of laboratory mice with a genetic mutation mimicking CS.

“We were able to visualize the fusion of lysosomes and endosomes as well as the release of endosome cargo outside the neuron,” said Matthew Pescosolido, first author of the paper who earned his doctorate in neuroscience. de Brown working in Morrow’s lab and is now a postdoctoral fellow in biology at Brandeis University. “This expulsion of endosomes was dramatically increased in CS cells.”

There are three main elements in the discovery of the team.

The first is that lysosomes in people with Christianson syndrome are functionally impaired and do not function as well as lysosomes in normal neurons. This is important, Morrow said, because it’s likely that CS is linked to other lysosomal disorders, a group of other childhood neurological diseases with defective lysosome function that include conditions such as Tay Sachs disease, Batten disease and Nieman-Pick disease, among others. A promising area of ​​research for these disorders is the use of gene therapy, Morrow said, and this could extend to CS as well.

“Knowing what’s going on in the cell in people with CS gives us an idea of ​​what gene replacement therapy would have to counteract to be beneficial,” Morrow said, adding that lysosome dysfunction may also be a factor in neurodegenerative diseases such as Alzheimer’s disease.

The second key observation described in the article is that the maturation of the endosome, which carries waste cargo, is also impaired – the endosome has difficulty fusing with the lysosome.

Third, the researchers found that these late-stage defective endosomes fuse with the cell’s plasma membrane and dump their contents there. Using advanced imaging tools such as time-lapse microscopy and total internal reflection fluorescence microscopy, they were able to see the cellular activity of endosomes ejected from neurons.

“This finding gave us a more complete picture of how the endocytic pathway responded to the loss of NHE6,” Pescosolido said. “This likely reflects, in part, a compensatory mechanism to get rid of waste outside the cell rather than funneling it to an altered lysosome, which would not be able to break down that waste. In the future, it will be interesting to see how these endosomal contents influence other neighboring cells.

These findings greatly broaden the focus of CS research, Morrow said, “It’s not that overacidification isn’t an important part of the story. But this article shows that this is not the whole story.

When Pescosolido was working under Morrow’s mentorship at Brown, he had the opportunity to meet CS-affected families, which he says was a great privilege.

“Our goal has always been to provide these families, as well as clinicians and researchers, with high-quality information about the causes and course of CS,” Pescosolido said. “It has been so rewarding to collect the stories of these families and to be able to provide them with a more complete understanding of the causes of CS.”

Morrow’s research team is currently extending its studies to families affected by CS, with the goal of integrating this basic knowledge into information about the natural history of the disease as well as an initiative to develop new treatments.

Other contributors to the study included Qing Ouyang, assistant professor (research) of molecular biology, cell biology and biochemistry at Brown; and Judy Liu, associate professor of neurology and molecular biology, cell biology and biochemistry and associate director of the Center for Translational Neuroscience.

The work was supported by National Institutes of Health grants R01NS113141, R01MH102418, R01MH105442, and R21MH115392.