nematodes Archives - Sanford Burnham Prebys

Tag: nematodes

Institute News

Do worms get stressed? We asked an expert

AuthorMiles Martin
Date

April 19, 2023

Nematodes under a microscope

The National Institutes of Health recognizes April as National Stress Awareness Month, with the goal of bringing awareness to the health impact of stress.

Stress comes in many forms—from the psychological stress we experience during difficult moments to the biological stress in our smallest cells. At Sanford Burnham Prebys, Assistant Professor Caroline Kumsta, PhD, uses small worms (nematodes) to study the negative relationship between cellular stress and aging (yes, aging can be stressful!). On the flip side, she’s also exploring how we can use small amounts of stress to improve health and potentially treat neurodegenerative diseases. 

We spoke to Kumsta about her research to learn more about how nematodes, stress and neurodegenerative diseases are all related.

Why do you work with nematodes?
Nematodes are very good for aging research because they have a short life span—only a few weeks—so we can measure the effects of aging within a reasonable amount of time. Another reason why we like these worms is because we can measure stress responses in more than individual cells. We can use nematodes to study broader, more systemic responses, as well as how stress responses are communicated from tissue to tissue. We can only see these effects if we look at how stress responses are orchestrated across the entire organism. Even though worms don’t look like us, a lot of the basic biological machinery we study is the same as in humans because stress responses evolved a long, long time ago.

How do worms help you study aging and cellular stress responses?
“What doesn’t kill you makes you stronger” is true in biology—in other words, small amounts of stress can actually be beneficial for organisms, including humans. We’re studying this idea in nematodes by giving them a small heat shock early in their lives, almost like giving them a few minutes in a sauna. The heat triggers stress responses in the worms at the cellular level, and one of these responses is that the worms’ cells induce a cellular recycling process, called autophagy. Autophagy recycles cellular components and helps keep cells healthy and free from debris. This is a beneficial process that helps increase the life span of the worms. My team is exploring how this process works and figuring out how we can use it to fight diseases.

How can your work in nematodes help us study human diseases?
Our main target is neurodegenerative diseases. One of the drivers of diseases like Alzheimer’s, Parkinson’s or Huntington’s disease is that proteins accumulate in the brain in aggregates or clumps. We’ve seen that nematodes that have had a heat shock early in their lives have reduced clumping of disease-relevant proteins. This is because when autophagy kicks in as a stress response, it helps slow the accumulation of these clumpy proteins. We’re ultimately looking for ways to boost the cellular recycling process in humans as a way to treat degenerative diseases. We can imagine heat therapy as a treatment intervention, and we are currently developing methods of measuring autophagy status in humans so that we will be able to test potential interventions. 

Institute News

Newly discovered cell stress pathway could hold therapeutic promise for diverse diseases

AuthorGuest Blogger
Date

January 5, 2015

Header image

This post was written by Janelle Weaver, PhD, a freelance writer.

When cells are faced with unfavorable environmental conditions, such as limited nutrient availability, the activation of adaptive stress responses can help protect them against damage or death. For example, stressed cells can maintain sufficient energy levels for survival by degrading and recycling unnecessary or dysfunctional cellular components. This survival mechanism, known as autophagy (literally, ‘self-digestion’), also plays key roles in a variety of biological processes such as development and aging, and is often perturbed in various diseases. Even though tight control of autophagy is key to survival, relatively little is known about the signaling molecules that regulate this essential process.

Sanford-Burnham researchers have made important progress in addressing this gap in knowledge by discovering that proteins called STK3 and STK4 regulate autophagy across diverse species. As reported recently in Molecular Cell, the newly identified mode of autophagy regulation could potentially have important clinical implications for the treatment of a broad range of diseases, including cancer, diabetes, Alzheimer’s disease, cardiac dysfunction, and immune-related diseases.

“Our discovery is fundamental to our molecular understanding of how autophagy is regulated,” said senior study author Malene Hansen, PhD, associate professor of the Development, Aging, and Regeneration Program at Sanford-Burnham. “Because impairment in the autophagy process has been linked to many disorders in humans, we believe that pharmacological agents targeting this novel regulatory circuit may hold great therapeutic potential.”

Critical kinases

Autophagy is a cellular recycling process involving a highly intricate and complex series of events. Cellular components such as abnormal molecules or damaged organelles are first sequestered within vesicles known as autophagosomes. These vesicles then fuse with organelles called lysosomes, which contain enzymes that break down various molecules. This fusion process results in the formation of hybrid organelles called autolysosomes, where the defective cellular components are enzymatically degraded and recycled. A protein called LC3 plays crucial roles in the formation of autophagosomes and the recruitment of dysfunctional cellular components to these vesicles. The signaling events that coordinate LC3’s various functions in autophagy have not been clear, but new research from the Hansen lab now proposes a novel and essential role for the mammalian Hippo kinases STK3 and STK4 in regulating autophagy by targeting LC3 for phosphorylation.

In their study, Hansen and her team describe that deficiency in both STK3 and STK4 impairs autophagy not just in mammalian cells, but also in nematodes and yeast. When exploring how the kinases regulate autophagy in mammalian cells, the researchers discovered that phosphorylation of LC3 by STK3 and STK4, specifically on the amino acid threonine 50, is critical for fusion between autophagosomes and lysosomes—an essential step in the autophagy process. “Collectively, the results of this study strongly support a critical and evolutionarily conserved role for STK3 and STK4 in regulating autophagy, by phosphorylating the key autophagy protein LC3, at least in mammalian cells,” Hansen said.

Killing bacteria

Previous studies have shown that STK4 also plays a role in regulating antibacterial and antiviral immunity in mammals, including humans. Moreover, autophagy is known to play a role in the clearance of intracellular pathogens. “These findings, taken together with our discovery that deficiency in STK3 and STK4 severely compromises autophagy, led us to test whether STK4 also plays a role in antimicrobial immunity through its function in autophagy,” said lead study author Deepti Wilkinson, Ph.D., a postdoctoral fellow in Hansen’s lab.

To test this notion, the researchers collaborated with Victor Nizet MD, professor of Pediatrics and Pharmacy  at UC San Diego and found that indeed mouse embryonic cells deficient in both STK3 and STK4 were unable to efficiently kill intracellular group A streptococci—bacteria known to be cleared by autophagy. However, an LC3 mutation that resulted in constant phosphorylation at threonine 50 restored the ability of the STK3/STK4-deficient cells to kill the bacteria. “This finding suggests that the same STK4-LC3 signaling pathway involved in autophagy also contributes to the response of mammalian cells to infection with intracellular pathogens and could play a role in human immune-related disease,” Wilkinson said.

Correcting defects

Moving forward, the researchers plan to further probe the molecular mechanisms by which STK3 and STK4 regulate autophagy. They will also investigate the therapeutic implications of the STK3/STK4 signaling pathway for tumor suppression as well as immune-related disorders such as bacterial and viral infections. “Understanding how autophagy works and why it sometimes stops to function optimally is essential for fighting diseases such as cancer, diabetes and neurodegeneration,” Hansen said.

“We have made a major contribution towards this endeavor by showing that STK3 and STK4 play an essential role in keeping the process of autophagy running smoothly by directly phosphorylating the key autophagy protein LC3. We hope our discoveries will lead to the development of effective drugs that can help correct autophagy defects that commonly occur in these diseases,” added Hansen.

A copy of the paper can be found at: http://www.ncbi.nlm.nih.gov/pubmed/25544559