Reactive Glia-Derived Neuroinflammation: a Novel Hallmark in Lafora Progressive Myoclonus Epilepsy That Progresses with Age

Mol Neurobiol. 2020 Mar;57(3):1607-1621. doi: 10.1007/s12035-019-01842-z. Epub 2019 Dec 5.


Lafora disease (LD) is a rare, fatal form of progressive myoclonus epilepsy. The molecular basis of this devastating disease is still poorly understood, and no treatment is available yet, which leads to the death of the patients around 10 years from the onset of the first symptoms. The hallmark of LD is the accumulation of insoluble glycogen-like inclusions in the brain and peripheral tissues, as a consequence of altered glycogen homeostasis. In addition, other determinants in the pathophysiology of LD have been suggested, such as proteostasis impairment, with reduction in autophagy, and oxidative stress, among others. In order to gain a general view of the genes involved in the pathophysiology of LD, in this work, we have performed RNA-Seq transcriptome analyses of whole-brain tissue from two independent mouse models of the disease, namely Epm2a-/- and Epm2b-/- mice, at different times of age. Our results provide strong evidence for three major facts: first, in both models of LD, we found a common set of upregulated genes, most of them encoding mediators of inflammatory response; second, there was a progression with the age in the appearance of these inflammatory markers, starting at 3 months of age; and third, reactive glia was responsible for the expression of these inflammatory genes. These results clearly indicate that neuroinflammation is one of the most important traits to be considered in order to fully understand the pathophysiology of LD, and define reactive glia as novel therapeutic targets in the disease.

Keywords: Activated microglia; Lafora disease; Neuroinflammation; Progressive myoclonus epilepsy; Reactive astrocytes; Transcriptome.

MeSH terms

  • Age Factors*
  • Animals
  • Disease Models, Animal
  • Disease Progression
  • Glycogen / metabolism
  • Inclusion Bodies / metabolism
  • Lafora Disease / genetics
  • Lafora Disease / metabolism*
  • Mice, Knockout
  • Myoclonic Epilepsies, Progressive / genetics
  • Myoclonic Epilepsies, Progressive / metabolism*
  • Neuroglia / metabolism*
  • Oxidative Stress / physiology
  • Protein Tyrosine Phosphatases, Non-Receptor / metabolism*


  • Glycogen
  • Protein Tyrosine Phosphatases, Non-Receptor