By Emily Leclerc | Waisman Science Writer
At a Glance
- Cells, like factories, have built in quality control systems to make sure that proteins are built correctly. If they fail, it can have widespread and varied consequences.
- The specific quality control pathway in the endoplasmic reticulum (ER) (an organelle inside the cell that builds proteins) called the ER acetylation pathway, is especially important for neuron health. When it is disrupted, it is linked to rare forms of autism and progeria.
- New animal model studies from Waisman researchers confirm these links. When the pathway’s final inspectors, enzymes called acetyltransferases or ATases, are overactive in neurons, the animal model shows autism-like behaviors. When they’re overactive throughout the body, the animal model develops a progeria-like condition.
- This research may open the door for potential treatments. Because ATases are the last step in the pathway, blocking them could theoretically fix problems anywhere along the system.
Just like a car factory relies on inspectors to ensure that every vehicle is built correctly, cells depend on internal quality control systems to keep proteins functioning as they should. New research from Waisman Center investigator Luigi Puglielli, MD, PhD, professor of medicine at the University of Wisconsin-Madison, reveals that disruptions in one such system—the endoplasmic reticulum’s acetylation pathway—can lead to rare forms of autism and progeria, offering fresh insights into the cellular roots of these complex conditions.
The endoplasmic reticulum (ER), an organelle that makes and modifies proteins that will either be used in the cell membrane or secreted outside of the cell, is much like a car manufacturing line, although the ER builds proteins instead of cars. Both car factories and the ER have robust quality control systems that inspect the product at multiple points along the process to ensure that they are built correctly and functioning properly. In the case of proteins, that means checking that they are folded into the correct shape and, if they aren’t, tagging them for destruction.
The ER acetylation machinery or pathway is a component of the ER’s quality control system. It was discovered by Puglielli in 2007 and is crucially important for healthy neurons. Puglielli has shown that disruptions at almost any point along the pathway results in rare forms of autism and other conditions as well. “The fact that the mouse models that target each individual element of this pathway reproduce what is suggested by human studies also provides strength to our hypothesis that the whole pathway is linked,” Puglielli says. It seems that without that quality control system in place, cells are unable to function as they should.
Two new papers recently published by Puglielli add additional evidence to support this theory. In humans, some genetic duplication events have been linked with the development of autism. One rare duplication that has been connected involves genes that produce enzymes that are crucial last steps of the acetylation pathway. But this had not been validated in animal models yet. These two papers address that gap.
Both papers look at what happens in mouse models when the last step of the acetylation machinery is overexpressed, like it would be in a duplication event, in two different contexts. The last step involves enzymes called acetyltransferases or ATases. They are the final inspectors at the end of the manufacturing line. Before a protein can leave the ER, the ATases have to tag it with an acetyl group. This tells the ER that the protein is shaped correctly, functioning as it should, and ready to go.
In the first paper, Puglielli developed a mouse model to study the consequences of ATase overexpression when it was only in neurons. On behavioral analysis, the mice displayed autism-like behaviors that were similar to the models used in studying disruptions to other parts of the pathway. Additionally, the neurons in the models’ brains showed altered neuronal shape and synaptic structure and function. Synapses are the connections between neurons that they use to communicate with one another. These results reinforce the association between ATase gene duplications and autism.
The second paper developed a model to study what happens when the ATase overexpression is body wide rather than localized to just neurons. Those mice developed a severe progeria-like condition. Progeria is a rare genetic disorder that causes premature aging. It also strengthens this pathway’s link to disease.
“These two papers demonstrate that the acetylation pathway we have identified and characterized is really involved in these conditions and diseases, which underscores what is emerging in human studies,” Puglielli says. “The models that investigate the individual parts of the pathway show that disturbances in the homeostasis of this pathway is what is causing these outcomes.”
Understanding the ATase’s role in the pathway and what happens when they are disturbed is important knowledge on its own but it also provides an important opportunity for potential future therapeutics. “Theoretically, because the ATases are the last part of the pathway, if you block them you could rescue issues that are caused at any point along the pathway,” Puglielli says. “That has the potential to address several different conditions with one therapeutic.”
From here, the research opens up considerably. There are multiple cellular inputs that feed into this pathway that need further study alongside investigating current compounds or finding novel ones that can inhibit the ATases. “We do already have some compounds that inhibit them, but the idea now is to find more. And now that we have the right models, we can start researching if any of them are capable of rescuing the autism behaviors in each mouse,” Puglielli says.
This research is still very early stage. It has a long way to go before it could potentially result in any sort of treatment or therapeutic. Additionally, it is very specialized to the rare cases of autism where duplications involving this pathway are involved. Even so, the increase in knowledge and its future potential are important scientific steps forward.
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