Lafora disease is an inherited neurodegenerative condition that initially develops with seizures in adolescence and evolves with progressive degeneration of the nervous system to death, about ten years after its onset. It is characterized by the accumulation of abnormal glycogen aggregates called Lafora bodies in the brain. There is currently no treatment for this condition, although some therapies are being tested in clinical trials.
Led by Dr. Joan Guinovart, emeritus professor of the University of Barcelona (UB) and also group leader of CIBERDEM, the Metabolic Engineering lab at IRB Barcelona has discovered that Lafora bodies that accumulate in astroglial cells, which are essential for the proper functioning of the nervous system, are responsible for the epilepsy and neurodegeneration associated with the disease. IBEC researchers Arnau Hervera and José Antonio del Río; Group Leader of the Molecular and Cellular Neurobiotechnology and full professor of the Department of Cell Biology, Physiology and Immunology of the UB, associated member of the Institute of Neurosciences, and member of CIBERNED, also contributed to this work.
For this study, Dr. Guinovart’s group generated a mouse model of Lafora disease, in which they prevented glycogen from accumulating in astroglial cells. They found that these mice did not develop neurodegeneration.
«Our contribution to the study discriminates the particular relevance of the glycogen accumulation in astroglia and neurons in the appearance of the epileptic seizures in these mice models of the disease» explain Hervera and Del Río.
For years, it was believed that the disease was caused by the accumulation of Lafora bodies only in neurons, but now we have shown that neurodegeneration is caused by accumulations in glial cells, says Dr. Jordi Duran, co-director of the study.
«This discovery has important implications for the design of treatments for the disease and we now intend to investigate the mechanism by which glycogen deposits cause this damage. We will also study the possible role of this pathological mechanism in other neurodegenerative diseases,» explains Dr. Duran.
A consortium supported by the association of affected families
This project has been developed within the framework of a global consortium for the study of Lafora disease, coordinated by the University of Kentucky in the US. In 2016, the consortium received $7.7 M from NIH (U.S. National Institutes of Health) for a period of five years. The consortium was promoted by Chelsea’s Hope, an association of families in the US affected by Lafora disease, which in 2014 brought together leading specialists to foster research into the disease. The study also involved the laboratory led Prof. Matthew Gentry (at the University of Kentucky).
Jordi Duran, Arnau Hervera, Kia H Markussen, Olga Varea, Iliana López-Soldado, Ramon C Sun, Jose Antonio del Río, Matthew S Gentry & Joan J Guinovart
Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease. Brain (2021) DOI: 10.1093/brain/awab110