2025 HDBuzz Prize: On the Frontlines: Trusting the Hall Monitors of the Cell

Think about the last time you were stressed. What did you do to feel better? For many of us, it’s talking through our frustrations. Getting rid of things that stress out our cells also requires good communication. The central communicators? Chaperone proteins. Chaperone proteins are just like the chaperones at a school dance. They direct misbehaving proteins to where they need to go and keep them from causing more chaos in the cell. Proteins can be misbehaving in cells for many different reasons, but in diseases like HD, the expanded huntingtin protein is thought to misbehave because it isn’t folded properly and clumps together. 

A study identified the co-chaperone SGTA as an expanded huntingtin interactor in HD model cells and mice. Co-chaperones are like the hall monitors that report to chaperones. SGTA is potentially a promising therapeutic target because it is not essential for cellular processes and increases survival of patients of other protein misfolding diseases. Let’s get into this study and what they found. 

Finding the Troublemakers

In HD, expanded huntingtin clumps together into groups of misfolded proteins called aggregates. Chaperones target misfolded proteins to minimize the chaos in the cell. Expanded huntingtin aggregates are like magnets for chaperones. Despite this, chaperones fail to control the chaos caused by expanded huntingtin aggregates.

This is a key problem with using chaperones as a therapeutic target, but there are other issues too. Like the chaperones at a school dance, catching the chaos is not their only job, they also have to setup the dance. Chaperones help make new proteins, direct traffic in cells by sending specialized proteins to specific locations, and clean up by targeting old and damaged proteins to the cell’s trash can. Boosting the amount of a chaperone with a therapy doesn’t seem to help in HD. Having too many chaperones can be too much of a good thing and instead of productively removing the problem, we’ve introduced more chaos. 

Getting Caught by the Hall Monitors

Here’s the good news. There’s a subset of helper proteins called co-chaperones that work with chaperones. The role of co-chaperones is to serve as the first response. Like hall monitors, they find the sneaky misfolded proteins and stop them from causing more problems. The sneaky protein is reprimanded by the co-chaperone and delivered to the chaperone. The chaperone is ultimately who decides what to do with the protein, but the co-chaperone often helps the chaperone find the protein, hence the name co-chaperone.

A study has identified the co-chaperone SGTA to be of particular interest as a new star hall monitor. Kubota and colleagues found that SGTA associates with the huntingtin aggregates in HD model cells and mice. They also found that SGTA associates with a large proportion of the huntingtin in cells models of HD that we would expect to be in the aggregated stage. Even though aggregates act like magnets for cochaperones like SGTA, the co-chaperone needs to be in range of the aggregate. The authors propose SGTA is acting on the aggregate and even identify the region of SGTA molecule that sticks to the huntingtin clumps. Now we’ve identified a hall monitor capable of reprimanding huntingtin before it takes it to the chaperone.

Strengthening the Frontlines

The big question now that we know SGTA interacts with huntingtin clumps is whether we can use it as a target for developing new medicines for HD. Researchers increased the amount of SGTA in HD model cells to see if it would reduce huntingtin clumps or cause more chaos. They found that increasing SGTA made expanded huntingtin less aggregated and more soluble. This suggests that SGTA isn’t just getting stuck on the huntingtin magnet but is intentionally acting on sneaky huntingtin.

Boosting SGTA to change huntingtin solubility is a major finding. Huntingtin aggregates are big insoluble protein clumps, and SGTA overexpression shifts expanded huntingtin toward a more soluble state. SGTA seems to specifically target small immature aggregates rather than large mature ones. Because of this preference, SGTA may help determine whether immature or mature aggregates should be targeted to treat HD.

What’s Next

This study shows the importance of trusting the hall monitors of the cell. Researchers found not only that SGTA binds to expanded huntingtin, but also that when you increase the amount of SGTA in the cell, the properties of expanded huntingtin change to a less aggregated state. This suggests that SGTA is acting on expanded huntingtin to decrease its aggregation.

Where do we go from here? Increasing our cellular hall monitors shows promise as a therapeutic target, but there is still lots of work to be done. What is SGTA doing to decrease aggregation? Why is increasing the amount of it effective? Is it working with a chaperone or acting all on its own? These are vital questions for future research.

Summary

• Chaperones target misbehaving proteins to prevent further chaos to the cell.
• In HD, expanded huntingtin misbehaves into aggregates that are not effectively managed by chaperones.
• Early studies find the co-chaperone SGTA to interact with expanded huntingtin.
• Increasing the amount of SGTA reduces the aggregation of expanded huntingtin.
• Co-chaperones may serve as an underutilized therapeutic target for managing HD.

Learn More

Original research article, “SGTA associates with intracellular aggregates in neurodegenerative diseases” (open access).

Meet this 2025 HDBuzz Writing Competition Winner

Chloe is a PhD candidate in the lab of Dr. Emily Sontag in the department of Biological Sciences at Marquette University. Her dissertation work focuses on how quality control proteins interact with the huntingtin protein associated with HD when mutated. She hope this work can contribute to future therapeutics.

This year, the HDBuzz Prize is brought to you by the Hereditary Disease Foundation (HDF), who are sponsoring this year’s competition.