Yu Yamaguchi Archives - Sanford Burnham Prebys
Institute News

This enzyme is one of the hardest working proteins in the body

AuthorMiles Martin
Date

October 21, 2021

Researchers from Sanford Burnham Prebys have shown that a protein they identified plays a major role in the breakdown of hyaluronic acid, a compound found in the scaffolding between our cells. The findings, published recently in the Journal of Biological Chemistry, could have implications for epilepsy, cancer and other human diseases associated with hyaluronic acid and similar compounds.

They also shed light on one of the most active biochemical processes in the body. 

“Our body turns over hyaluronic acid at an extremely rapid rate, far faster than the other compounds surrounding our cells,” says senior author Yu Yamaguchi, MD, PhD, a professor in the Human Genetics Program at Sanford Burnham Prebys.

Hyaluronic acid, a common ingredient in cosmetic anti-aging products, is a one of several large sugar molecules known as glycosaminoglycans (GAGs). These are found naturally in the extracellular matrix, the complex network of organic compounds surrounding our cells that gives structure to our tissues. In addition to its structural role, the extracellular matrix is involved in regulating the immune system and is critical in the early development of connective tissues like cartilage, bone and skin.

“The extracellular matrix is found in every organ and tissue of the body, and malfunctions in its biochemistry can trigger or contribute to a variety of diseases, some of which we don’t even know about yet,” says Yamaguchi. His team studies how GAGs affect childhood diseases including congenital deafness, epilepsy and multiple hereditary exostoses, a rare genetic disorder that causes debilitating cartilage growths on the skeleton.

Hyaluronic acid is also known to be correlated with several health conditions, depending on its concentration in certain tissues. Reduced levels of hyaluronic acid in the skin caused by aging contribute to loss of skin elasticity and reduced capacity to heal without scarring. Levels of hyaluronic acid in the blood dramatically increase in alcoholic liver disease, fatty liver and liver fibrosis. In addition, hyaluronic acid levels have been correlated with increased tumor growth in certain cancers.

“These compounds are literally everywhere in the body, and we continue to learn about how GAG’s influence disease, but there’s also a lot we still don’t know about how these molecules are processed,” says Yamaguchi, “Research like this is about understanding what’s happening at the molecular level so we can later translate that into treatments for disease.” 

For this study, the team focused on a protein called TMEM2, which they had previously found to break down hyaluronic acid by cutting the longer molecule into manageable pieces for other enzymes to process further. Using mice as a research model, they selectively shut off the gene that codes for TMEM2 and were able to successfully measure precisely how much the absence of TMEM2 affects the overall levels of hyaluronic acid.

The answer: a lot.

“We saw up to a 40-fold increase in the amount of hyaluronic acid in the study mice compared to our controls,” says Yamaguchi. “This tells us that TMEM2 is one of the key players in the process of degrading this compound, and its dysfunction may be a key player in driving human diseases.” 

The team further confirmed this role of the TMEM2 protein by using fluorescent compounds that detect hyaluronic acid to determine where the TMEM2 protein is most active. They found the most activity on the surface of cells lining blood vessels in the liver and lymph nodes, which are known to be the main sites of hyaluronic acid degradation. 

“These findings refine our understanding of this critical biochemical process and set us up to explore it further in the interest of developing treatments for human diseases,” says Yamaguchi. “Hyaluronic acid is so much a part of our tissues that there could be any number of diseases out there waiting to benefit from discoveries like these.”

Institute News

Families find hope at our 10th Annual Rare Disease Day Symposium

AuthorMonica May
Date

March 25, 2019

The unofficial theme of Sanford Burnham Prebys’ 10th annual Rare Disease Day symposium can be summarized in one word: hope. 

This year’s event focused on rare bone disorders and bone cancers, with a special emphasis on a condition called multiple hereditary exostoses (MHE) that causes numerous bone tumors in children. Until now, children with MHE had only one treatment option: repeated surgeries to remove these tumors. 

Now, the first medicine, called palovarotene, that may be able to slow or halt this bone growth is being tested in a clinical trial—potentially saving these children from a lifetime of painful surgeries. Yu Yamaguchi, MD, PhD, symposium chair and professor in Sanford Burnham Prebys’ Human Genetics program, participated in the key research needed in order for the clinical trial to begin.

“For the first time, a diagnosis doesn’t feel like a life sentence,” says Greta Falkner, who attended the symposium with her 8-year-old son, Jackson Falkner. Jackson has MHE and has undergone 13 surgeries to date. “Today we have hope for a cure.”

The launch of a study evaluating palovarotene as an MHE treatment is the result of decades of hard work and collaboration between scientists, clinicians, Clementia Pharmaceuticals (now Ipsen) and the MHE Research Foundation—a patient advocacy and support group. 

The symposium featured an all-star lineup of distinguished speakers in the field of skeletal biology and MHE research, including keynote speaker Henry Kronenberg, MD, of Massachusetts General Hospital and Maurizio Pacifici, PhD, of Children’s Hospital of Philadelphia, whose research formed the scientific rationale for the use of the drug in MHE. The event was sponsored by the MHE Research Foundation and Clementia Pharmaceuticals. 

“We are so grateful that Sanford Burnham Prebys holds this Rare Disease Day symposium to bring together all the important players in rare disease drug discovery: scientists, doctors, families and drug companies. It is literally ‘bench to bedside’ at one event,” says Sarah Ziegler, who co-founded the MHE Research Foundation with Craig and Susan Eaton after Sarah’s son was diagnosed with MHE in 1993 (when little to no information was available on the disease). “Foundations like ours rely on the research of scientists like Drs. Yamaguchi and Pacifici to find new medicines for patients—and the arrival of the first potential treatment for MHE is the perfect example of the power of this research.” 

Multiple parents and children with MHE, some of whom are enrolled in the clinical trial, attended the event. For most of these children, this was the first time they’d met another person with their condition. 
 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

Institute News

Year in review: Top stories in 2017

AuthorSusan Gammon
Date

January 9, 2018

In the last 12 months, SBP scientists published 338 scientific papersthat’s almost a paper a day. We are proud of this impressive achievement, and equally proud of the quality of research in these scientific studies. Whether you are seeing them for the first time or coming back for another look, check out the most popular stories from SBP’s researchers in 2017.

  1. Scientists take a deeper dive into cellular trash
    Malene Hansen, PhD, led the first-ever comprehensive analysis of autophagy in a living animal during aging. The study was published in eLIFE.  
  2. Drug short-circuits cancer signaling
    A drug that zeroes in on mutated nuclear receptors found in cancer will soon be entering Phase 1 clinical trials at the Dana Farber Cancer Center for patients with colorectal cancer. Research by Xaio-kun Zhang, PhD, describes how the targets cancer but leaves normal proteins alone.
  3.  Biomarker may predict early Alzheimer’s disease
    Erkki Ruoslahti, MD, PhD, has discovered a new approach to detect Alzheimer’s disease at its earliest stages. His research team found a biological marker, or biomarker, that’s associated with brain inflammation—a trigger for the Alzheimer’s process, which takes many years to produce symptoms. 
  4.  Steps toward a promising therapy for a rare bone disease
    Yu Yamaguchi, MD, PhD, led a study proving fresh insight into the mechanism of multiple hereditary exotoses (MHE)—a rare disease that causes the growth of multiple benign bone tumors. The research opened the door for testing the drug palovarotene in Phase 2/3 clinical trials for patients with MHE.
  5. New insights into bipolar disease
    An international collaborative study led by Evan Snyder, MD, PhD, was first to explain the molecular basis of bipolar disease and may support the development of a diagnostic test for the disorder. The research may also help scientists develop tools to predict the likelihood of patient response to lithium treatmenta highly effective drug that works in only 30% of bipolar patients.
Institute News

Genes and proteins go hand-in-hand

AuthorBill Stallcup, PhD
Date

July 14, 2017

Thanks to huge improvements in DNA sequencing technology, scientists have identified almost all the genes present in humans. Despite this achievement, there are still thousands of genes whose functions remain a mystery. Since genes are basically blueprints for making the proteins needed to run our cellular machinery, connecting genes with the specific functions of their encoded proteins is a critical next step in using genomic information to solve health-related problems.

Bridging the gap between gene sequence and protein function is the topic of a study published in the Journal of Biological Chemistry by Yu Yamaguchi, MD, PhD, professor at SBP. According to Yamaguchi, “There has been a long-standing mystery concerning the processing of hyaluronic acid (HA), a large sponge-like molecule required to maintain proper spacing between neighboring cells. We had already learned a lot about how cells make HA, but the other equally important side of the equation is how HA is broken down, which is needed to prevent HA build-up that can cause tissue fibrosis.”

The Yamaguchi lab knew that HA degradation must be accomplished by enzymes that cut HA into smaller pieces for further processing. “However, none of the known HA-cutting enzymes had the ability to cut the very large HA that exists outside the cell”, explains postdoctoral fellow Hayato Yamamoto, MD, PhD, first author on the study. “We decided to search gene sequence libraries to identify other proteins that were not previously suspected to cut HA, but which were structurally similar to known HA cutters.”

Their search turned up transmembrane protein 2 (TMEM2), whose structure predicted that it would exist on the cell surface and would also be able to cut HA. “My job was then to determine whether or not this protein could live up to our predictions,” recalls Yamaguchi. “We were able to show experimentally that the protein really did exist on the cell surface and was able to cut large HA molecules into smaller fragments for further processing inside the cell.”

Read the paper here.

Institute News

Research may explain congenital deafness

AuthorJessica Moore
Date

March 15, 2017

If you’ve heard of hyaluronic acid (HA), it’s probably as an ingredient in cosmetic products meant to help keep skin moisturized. But HA—a polysaccharide, or long chain of sugars—is also a major component of the material that surrounds cells in almost every tissue. It’s particularly important in joints, where it’s part of the fluid that lubricates the cartilage ends of bones as they move against each other, and in the eyes, where it helps maintain the shape of the eyeball.

HA is broken down and replaced much faster than other molecules that make up the structure of tissues—one-third of all the HA in your body (about 15 grams in an average-sized human) is turned over each day. But despite its ubiquity and rapid turnover, how HA is degraded remained a mystery. The only enzymes known to cut it up are located inside cells, but HA is far too large to be taken into a cell whole.

That conundrum has now been untangled. Research from the lab of Yu Yamaguchi, MD, PhD, professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), has identified the enzyme that chops extracellular HA into pieces, a protein called TMEM2 (transmembrane protein 2).

“Until now, the function of TMEM2 was unknown,” says Yamaguchi. “We show that it specifically cleaves HA and none of the other polysaccharides that surround cells.”

The discovery, published in the Journal of Biological Chemistry, could help explain the seemingly unrelated effects of altering or inactivating the TMEM2 gene. Zebrafish lacking TMEM2 die as embryos because their hearts don’t develop properly, and mutations in TMEM2 have been linked to severe inherited deafness. That those presentations are so different is less perplexing now that we know that TMEM2 helps control levels of HA. HA is an important ingredient in cardiac jelly, the gelatinous tissue that fosters proper heart formation, and in the fluid in the inner ear that conducts sound waves.

“Our findings open the door to better understanding of an unknown number of disease states,” Yamaguchi adds. “The fact that eliminating the TMEM2 gene causes mortality suggests that it’s really important, but keeps us from seeing how it supports the function of various tissues later in life. To figure that out, we’re making mice that lack TMEM2 only in certain organs.”

Institute News

Closing in on the causes of Alzheimer’s disease

AuthorGuest Blogger
Date

April 5, 2016

This post was written by Nicole Le, a guest blogger.

Imagine if we could clear the brain of plaque that accumulates and causes Alzheimer’s disease (AD) as simply as having the plaque removed from our teeth? The body has a natural clearing mechanism in place to rid the brain of these deposits, but if this mechanism gets overwhelmed or disrupted, the plaques can accumulate and lead to neurodegeneration. Continue reading “Closing in on the causes of Alzheimer’s disease”