By Emily Leclerc | Waisman Science Writer
Cells make a lot of trash. Probably more than you’d think. So, cells have a trash disposal system that efficiently cleans up and recycles any waste that is produced. But when there are issues with the disposal system and trash builds up in the cell, that can lead to disease. This has led researchers to consider the trash disposal system as a target for potential disease treatments and therapies. New research from the Waisman Center reveals that stimulating a cell’s disposal system in specific places could potentially be an effective treatment route for diseases that are caused by trash accumulation, specifically misfolded proteins.
Waisman investigators Luigi Puglielli, MD, PhD, professor of medicine, and John Svaren, PhD, Vilas Distinguished Achievement Professor of Comparative Biosciences, recently published a study that showcases a new way to help clear away misfolded protein buildups specifically in a cell’s endoplasmic reticulum that are associated with Charcot-Marie-Tooth disease (CMT) by stimulating a cell’s trash disposal system. The paper, Spatial selectivity of ATase inhibition in mouse models of CMT disease, was published in the journal Brain Communications.
The endoplasmic reticulum (ER) is a structure found inside every cell in the body that is responsible for producing many of the proteins a cell needs to function. As part of the production process, proteins will fold into their final shape inside of the ER. To proteins, shape is everything. Only a properly folded protein can function correctly. A protein that folds into the wrong shape has to be diverted to the trash disposal system to be broken down and recycled. Misfolded proteins are tagged for the trash by the ER’s quality control system – the acetylation machinery being an important part of it.
The ER acetylation machinery, which was discovered and defined by Puglielli and his lab, ensures that proteins inside the ER are folded correctly and if they aren’t, it activates autophagy. Autophagy is one part of a cell’s trash disposal system. It is the process through which the cell breaks down waste and recycles it.
When there is a mutation in the genome that causes proteins being made inside the ER to misfold, they often collect together into clumps called aggregates. Autophagy has a tough time clearing away protein aggregates for multiple reasons. A new theory for potential treatments to conditions resulting from aggregates such as Charcot-Marie-Tooth disease (CMT), Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington’s disease, is to stimulate autophagy to help degrade and recycle the protein aggregates. The trick is finding a way to activate autophagy in the correct place.
“There is a lot of interest in using tools like biochemical compounds that stimulate autophagy to resolve disease because it can help cells to digest protein aggregates. Like helping to clean up the trash in the house,” Puglielli says. “If you have protein aggregates in the ER or another organelle we want to be able to activate autophagy and limit the activation to a specific place. For example, if you have trash in the kitchen, you don’t start cleaning the bathroom. You go right to the kitchen.” Generalized activation of autophagy can have a number of side effects that can be damaging to the cells and to the individual as a whole. Determining ways to activate autophagy exactly where it is needed will allow researchers to utilize its waste cleaning abilities while avoiding harmful side effects.
Puglielli focused on two proteins – acetyltransferase 1 (ATase1) and acetyltransferase 2 (ATase2)— that are a part of the acetylation machinery in the ER to see if they can be used to selectively stimulate autophagy inside the ER and nowhere else. ATase1 and ATase2 regulate the activation of autophagy inside the ER. By blocking the ATases, Puglielli was able to activate autophagy inside the ER. To determine if the ATases only stimulate autophagy inside the ER, Puglielli and Svaren, whose research focuses specifically on CMT, set up two different mouse models of CMT – one where the protein aggregates form outside the ER and another where they form within.
Charcot Marie Tooth disease, or CMT, is an inherited nerve disorder that impacts nerves in a person’s feet, legs, hands, and arms. There are several different types of CMT that are categorized by what type of genetic mutation an individual has. According to Svaren, roughly 10% to 15% of CMT cases are associated with protein misfolding caused by different mutations.
Puglielli found that when they stimulated autophagy by blocking the ATases, autophagy only activated inside the ER. In the mouse model where the protein aggregates formed outside of the ER, the aggregates were unaffected. “This system can discriminate between events inside the ER and outside the ER,” Puglielli says. This discovery establishes the ATases as the first target for addressing protein aggregates that form inside of the ER. It activates the cell’s trash disposal system and in one selective space.
This work provides important foundational information for potential personalized CMT therapies down the line – and potential therapeutic avenues for other conditions caused by protein aggregates. Cystic fibrosis – a genetic condition that causes often severe damage to the lungs, digestive system, and other organs – is also caused by protein aggregates inside of the ER. Puglielli’s discovery may provide another option for a potential treatment for this chronic condition. It also expands knowledge of selective autophagy activation that can be applied to a broader range of conditions where aggregates form in other places outside of the ER.
“The NIH (National Institutes of Health) said recently that there are 15,000 rare disorders. And a lot of dedicated foundations are focused on trying to find individual treatments for all of these disorders. But what if we can find common attack points for multiple rare disorders,” Svaren says. “Sometimes there are common mechanisms that occur in different cell types and organs that cause different diseases but are all based in one fundamental cause. If its something fundamental, like autophagy, you could potentially attack several diseases at the same time.”
While this work is far from being translated into actual therapies, the research doors it opens are important. From here, Puglielli wants to build an effective pipeline to work on finding a compound or drug suitable for clinical trials that accomplishes this selective autophagy through ATase blocking. That could take some time but he is excited by the prospect of translational research. Svaren looks forward to the opportunity to again work alongside Puglielli in pursuit of improved therapeutics for CMT and more.
“Puglielli really discovered this whole area himself and has developed the first pharmacology [research compounds] in this area as well,” Svaren says. “It has promise in a variety of diseases and it looks like it has real promise for CMT as well. That is exciting.”
This research was funded in part by the Charcot-Marie-Tooth Association – a nonprofit organization determined to bring researchers, clinicians, patients, and companies together to help accelerate the development of treatments and hopefully find a cure for CMT.
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