By Gillian Neimark

Adult Polyglucosan Body Disease (APBD) is one of 7,000 rare diseases in the U.S. There are currently no effective treatments for the challenging neurodegenerative disorder. That may change with the publication of a study that identifies two key proteins in the body which, when blocked or reduced, may actually prevent the disease from occurring.

The study – which was conducted over two years and was funded by the APBD Research Foundation and the National Institutes of Health – was published in November 2020 in the Annals of Clinical and Translational Neurology. The work was led by world-renowned pediatric neurologist Berge Minassian, MD, Chief of the Division of Child Neurology at the University of Texas Southwestern Medical Center in Dallas. The study followed mice engineered to have the most common mutation causing human APBD, and also engineered to reduce or stop production of two important proteins discussed below. Both proteins help the body build the sugar storage molecule glycogen, which is deformed in APBD sufferers. When either of these proteins were absent or reduced, mice were protected from the disease’s devastating impact.

Dr. Minassian explains, “Unlike replacing a missing gene, reducing the function of an existing gene, which is what is required here, is currently eminently feasible. We are now working to develop the required drug and hope to be able to finally have a treatment that completely alters the disease course in APBD.”

What the Research Showed Is Encouraging

APBD is caused by mutations in a single gene, GBE1 (the glycogen branching enzyme gene). This gene helps the body build glycogen, a form of glucose that is easily stored by the body. In healthy individuals, a single glycogen molecule can store as many as 55,000 glucose molecules in multiple chains that branch off its center. Glucose molecules can be rapidly broken off the chains when needed for energy or added back on for storage of excess glucose. In APBD—which is a form of Glycogen Storage Disease Type IV—the mutated gene instead results in a large amount of glycogen that is oddly shaped, with very long chains that contain fewer branches. This form cannot be easily used by the body and tends to build up, forming abnormal clumps called polyglucosan bodies. Over the long term, these polyglucosan bodies can damage cells, particularly those of the nervous system.

The Glycogen Synthase (GYS1) Gene

The researchers targeted the synthesis of glycogen in the body, theorizing that reducing glycogen would also reduce the number of damaging polyglucosan bodies. Two genes that make two proteins were studied. The first was the glycogen synthase (GYS1) gene, which helps build the long, linear chains in glycogen. The researchers hoped that by reducing glycogen synthase, they could correct the ratio between long, linear chains and branched chains in glycogen, thereby preventing deformed glycogen from being made. This rationale was supported by previous laboratory research in neurons that showed that inhibiting glycogen synthase does indeed lower polyglucosan bodies.

The Protein Phosphatase 1 Regulatory Subunit 3C (PPP1R3C) Gene

The second gene studied helps activate glycogen synthase and is called protein phosphatase 1 regulatory subunit 3C or PPP1R3C. The rationale behind targeting PPP1R3C was quite similar to the rationale behind targeting glycogen synthase. If glycogen synthase activity could be reduced, levels of elongated glycogen chains in the disease could also be reduced.

We all carry two copies of almost every gene in the body. The researchers knocked out only one copy of the glycogen synthase gene, because research has shown that mice with no glycogen synthase gene at all usually do not survive birth. For PPP1R3C, they bred mice deficient in either one or both copies of the gene and studied both sets of those mice.

The results were impressive. The APBD mice lost body weight, appeared hunched, had poor balance, and altered movement. They also had a shortened lifespan of approximately 12 months of age. In comparison, APBD mice deficient in one copy of glycogen synthase had normal body weights, balance abilities, activity levels, and walking patterns. These APBD mice deficient in glycogen synthase lived as long as normal healthy mice in the study—the full 24 months of the study. Similarly, the APBD mice that were deficient in one or two copies of PPP1R3C showed improved body weight, less hunching, and normal activity and walking. The APBD mice that were deficient in one copy of PPP1R3C lived only slightly longer than the APBD mice, but the mice deficient in both copies of the PPP1R3C gene lived until 22 months of age—a great improvement over the APBD mice, but still not a normal lifespan.

When brain, muscle, heart, and liver tissue were examined, the glycogen synthase-deficient APBD mice had fewer polyglucosan bodies in all those tissues. The PPP1R3C-deficient mice did well also—whether they had one or both copies of the gene knocked out. They showed lower levels of polyglucosan bodies in the brain, and lower levels of glycogen itself in muscle and the liver, compared to untreated APBD mice. Evidence of damage to neurons was also reduced.

Erin Chown, the article’s lead author states, “These research findings are important as they demonstrate that reducing glycogen synthase or PPP1R3C delays disease onset and slows disease progression in the APBD mouse model. This validation of glycogen synthase and PPP1R3C as effective therapeutic targets in mice is an important step towards the development of a treatment for individuals with APBD.”

Indeed, 1,700 FDA-approved compounds have been screened to find the ones that are able to reduce glycogen synthase activity and polyglucosan accumulation in APBD fibroblasts. This high throughput screening was accomplished by H. Orhan Akman, PhD at Columbia University Medical Center. Research has shown that guaiacol, 2-ethoxy phenol, and terpin are potential candidates, and they are being explored as therapies for APBD.

Research Applications Beyond APBD

This research extends earlier findings in another Glycogen Storage Disease, Lafora disease, which is a primary research interest of Dr. Minassian’s, and whose laboratory discovered the genes responsible for that disorder. Several mouse studies have shown that targeting these same two proteins helps protect against Lafora disease. The researchers highlight that these new findings have relevance to individuals suffering from other forms of Glycogen Storage Disease Type IV, and still other diseases in which polyglucosan bodies accumulate.

Jeff Levenson, co-president of the APBD Research Foundation adds, “Since its founding in 2005, the APBD Research Foundation has funded a group of talented and dedicated researchers. Their work has significantly advanced the understanding of the cause of APBD and potential cures for the disease, as well as for allied diseases. We are now focused on preparing our patient community for clinical trials of promising treatments on the horizon.”

Gillian Neimark is a veteran science journalist and author of adult and children’s fiction. A former contributing editor at Discover Magazine, she has also written for Scientific American, Science, Nautilus, Aeon, The New York Times, NPR, Quartz, Psychology Today, The Rumpus, Los Angeles Review, Borderlands, The Massachusetts Review, Cimarron Review, and Construction Literary Magazine.

EDITOR’S NOTE: Future articles in this series will focus on small molecule therapies and gene therapies which are being developed because of this groundbreaking research.

Get research news updates from us!

    Sign up for Updates: