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