Researchers from the University of Texas Southwestern Medical Center (UT Southwestern) and the University of Tokyo have recently published an article describing the mechanistic pathways of APBD, Lafora Disease (LD), and RBCK1-Deficiency disease (RD) — three glycogen storage disorders (GSDs). The study published in the journal Acta Neuropathologica presents novel biochemical and pathological firsts that enhance our understanding of APBD and inform efforts to develop effective therapies for this devastating disease. 

Dr. Sharmistha Mitra

The research was led by Dr. Sharmistha Mitra and Dr. Berge Minassian at the UT Southwestern Medical Center. In collaboration with Drs. Kazuhiro Iwai and Yasuhiro Fuseya from the University of Tokyo, the UT Southwestern researchers utilized mouse models of APBD, LD, and RD to study and compare the mechanism of polyglucosan body formation.   

APBD, LD, and RD are GSDs involving glycogen metabolism where structurally defective, abnormal glycogen (also called polyglucosan bodies) are precipitated in different tissues and cause severe pathologies. 

The researchers discovered that in APBD, LD and RD, skeletal muscle polyglucosan bodies form as two main types:

  • small and multitudinous type which the researchers named ‘pebbles’
  • giant types which the researchers named ‘boulders’

According to Dr. Mitra, “We found that this pattern of polyglucosan bodies is determined by the metabolic properties of the muscle fiber. Skeletal muscle fibers can be classified depending on their ATP sourcing. Fast glycolytic fibers have large volumes of glycogen, which they constantly break down into lactate to generate ATP quickly. This implies they cycle glycogen continuously. Slow oxidative fibers also store glycogen but utilize them minimally and use glucose for ATP generation.” 

Dr. Mitra added, “Our study showed that in the APBD, LD, and RD mouse models, ‘pebbles’ are formed in the fast glycolytic fibers while ‘boulders’ are formed in the slow oxidative skeletal muscle fibers.”

Furthermore, by analyzing APBD, LD, and RD mouse models of various ages, the researchers found that the largest amount of polyglucosan bodies occurred in APBD, accumulating in both male and female sexes equally. Comparatively, lower quantities of polyglucosan body accumulation were seen in LD and RD, where the amount also differs in male versus female skeletal muscles. 

These findings emphasize that the deficiency of the key glycogen metabolism pathway–related enzyme, GBE1, which is responsible for glycogen branching, has a greater and global impact on glycogen metabolism compared to the deficiencies of the accessory enzymes such as malin/laforin deficiency (LD) or RBCK-1 Deficiency. Intriguingly, in their biochemical studies, they found the oxidative myofibers, which showed occasional ‘boulders’ are relatively protected from polyglucosan body accumulation, in part, through highly increased GBE1 enzyme expression, once again highlighting the physiological importance of this critical enzyme in glycogen biology and polyglucosan body generation. 

Another striking observation in this study was the finding of severe tissue inflammation, macrophage invasion, and necrosis in the 7-month-old APBD mouse model, which was not seen in LD or RD, even at 12 months of age. This implies and confirms that polyglucosan bodies are heavily cytotoxic in nature. In both muscle and liver of APBD mice, it was seen that once polyglucosan body accumulation exceeded a certain amount, it invoked severe inflammatory responses recruiting macrophages, possibly to digest the insoluble aggregates. A failure to do the latter, ultimately, caused severe tissue necrosis. This observation has pathophysiological and therapeutic significance suggesting that APBD therapies will need be directed at either preventing polyglucosan body formation or digesting the polyglucosan bodies by utilizing external agents (such as antibody-enzyme fusion to degrade polyglucosan bodies) but not by activating intrinsic cellular degradation pathways such as autophagy. 

Overall, this work describes important mechanistic advances in the field of APBD research. Additionally, it opens up multiple new avenues towards understanding glycogen metabolism, a critical cellular pathway that controls important neurological and neuromuscular functions and disease. 

Editor’s Note: Research Highlights is an ongoing feature in our newsletter. It is focused on scientific publications of interest to our community. Our thanks to Dr. Sharmista Mitra for sharing her research with us in the May 2024 edition of our e-newsletter!