Tuning the Proteasome and its Effect on Health
Nic Lehrbach, Proteasome Researcher
Like any big city, Dr. Nic Lehrbach’s hometown of Sydney, Australia, was in a constant state of change. Old buildings would come down and almost just as quickly new ones would go up. Important to any city’s growth is construction, but just as important is controlled demolition. It’s difficult to grow with derelict buildings getting in the way. The same concept applies to our cells as they construct proteins.
These little biological machines underlie nearly every function of a cell, including muscle movement, neuronal communication, cellular division and so much more. But what happens when a protein molecule has outstayed its usefulness? Maybe it’s worn out and no longer works properly. Or, like bricks pulled from one building to use in another, perhaps its constituent parts could be better used elsewhere.
Breaking down unwanted proteins is the responsibility of a large molecular machine called the proteasome. If the proteasome’s activity is disrupted, the consequences can be disastrous for a cell. Too little activity and old proteins will start to build up, disrupting the activity of the cell and possibly leading to cell death. In worse-case scenarios, a sluggish proteasome can cause irregular cell division and lead to cancer. Too much proteasome activity, and the cell breaks down proteins it still needs. The correct balance is crucial and what makes Lehrbach so excited to uncover the details of this important biological phenomenon. With enough understanding, researchers could take control of the proteasome therapeutically.
Both of Lehrbach’s parents were biologists. Lehrbach joked that at first this made him want to pursue an unrelated path — but despite his rebellious spirit, he enjoyed the subject too much.
“In high school, chemistry and biology were my favorite subjects. I knew it was what I loved to do,” Lehrbach said.
He specialized in molecular biology and genetics when he attended university.
“What I really loved about genetics is the way that it always boils down to little logic puzzles. I love going through the reasoning to work out what's actually happening,” Lehrbach said.
For his Ph.D., he joined the developmental biology program at the University of Cambridge in the United Kingdom. It was there he first became interested in understanding the genetic underpinnings of aging. While aging and the gradual degradation of cellular function seem like an inevitable part of life, Lehrbach was excited by the discovery that some aspects of aging are surprisingly flexible.
“Aging seems to be under some kind of genetic control,” he said. “We know in certain organisms we can get mutations that increase their lifespan.”
In the case of a small worm called Caenorhabditis elegans, researchers found that certain mutations could make the worms live up to 10 times longer than usual, increasing their lives from just a few weeks to several months.
“It's an incredible change in lifespan,” Lehrbach said. “And I wanted to understand how it all worked.”
One aspect of this change in lifespan turned out to be changes in the proteasome’s regulation of protein degradation. In humans, the buildup of damaged or unwanted proteins has been correlated with numerous disorders, including the age-related neurodegenerative diseases Alzheimer’s and Parkinson’s. Even in healthy people, the capacity to degrade unwanted proteins decreases with age, which can lead to problematic protein build-up.
“In terms of aging, the big hypothesis is that boosting the proteasome would confer benefits during aging and increase lifespan,” Lehrbach said.
The discoveries yet to be made into the proteasome's function, and the substantial health impacts of these discoveries, motivate Lehrbach’s lab at Fred Hutch. Beyond just aging, his team is working to understand all aspects of protein regulation and the health consequences when the process goes awry. This includes studying how cells ensure that proteins are expressed at the right levels and how they’re removed when they become unwanted or damaged.
To find answers to these big questions, the lab uses the same tiny worm that first got Lehrbach interested in studying genetics, C. elegans. This tiny animal is an exceptional model system for scientists trying to understand many aspects of our biology because so much of their fundamental biology is shared with humans, including how their cells regulate protein production and degradation.
Using these worms, Lehrbach can genetically tune the proteasome’s function up and down.
“There are benefits to understanding how to modulate it in both directions,” Lehrbach said. “In the case of cancer treatment, you actually want to stop its function.”
"I’m working to shed light on the mechanisms by which cancer cells can become resistant to proteasome inhibitor drugs."
Protein buildup can be just as detrimental — or even deadly — to cancer cells as it is to healthy cells. Proteasome-inhibiting drugs can kill off tumor cells and are regularly prescribed to treat certain cancers, but they can become less effective over time.
"I’m working to shed light on the mechanisms by which cancer cells can become resistant to proteasome inhibitor drugs," Lehrbach said.
Understanding how cancer cells develop resistance to these treatments would greatly inform our understanding of how the proteasome functions and could lead to improved drugs that help ensure that patients stay cancer free.
Boosting proteasome function may be critical in the case of other health issues. For many years there was a mystery as to why individuals with mutations to a gene called NGLY1 had severe developmental and behavioral deficits, Including difficulty walking and talking.
“No one could work out why lacking this one gene would have all these effects and connect to all these symptoms,” Lehrbach said.
C. elegans helped him crack a key component of this mystery. Using the worms, Lehrbach identified that the mutation’s downstream effects ultimately harm the proteasome.
“This meant that patient’s cells can't maintain appropriate levels of proteasome activity, and it's this kind of proteasome deficiency that probably causes a lot of the symptoms,” he said.
Unwanted and damaged proteins build up in cells and impede their proper function. Lehrbach is now working to explore avenues for boosting proteasome activity as a possible therapy for people with mutations in NGLY1.
The promise of where his discoveries may lead motivates Lehrbach.
“My favorite thing about research is sharing in the thrill of discovery,” he said. “I love those days when someone comes into my office with a confusing result that sends our research in a new direction. I am so excited to see where our exploration of the proteasome will take us in the coming years.”
— By Matthew Ross, Feb. 2, 2023
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