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

Abstract

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 the 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 three 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.

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration

“…Although the primary cause of PMEs is different in each case, recent reports suggest that oxidative stress and neuroinflammation are common traits in all these conditions [161][162][163]. This reinforces the idea that oxidative stress and neuroinflammation are at the crossroad of rare neurodegenerative disorders.…”

“…Recently, we have analyzed by RNA-Seq technology the genes that were differentially expressed in the brain of Epm2a −/− and Epm2b −/− mice in comparison to control animals and observed that Epm2a −/− and Epm2 −/− mouse brains overexpress a common set of genes mostly related to inflammation [162]. We also defined that reactive glia was responsible for the expression of these genes.…”

Neuroinflammation and progressive myoclonus epilepsies: from basic science to therapeutic opportunities

“…These results clearly indicated that neuroinflammation is an important trait to be considered in order to fully understand the pathophysiology of LD (Ref. 37).…”

Neuron-Glia Interactions in Neurodevelopmental Disorders

“…Epilepsy is a common symptom in patients with brain tumors, head injuries, and genetic diseases [ 89 , 94 , 139 , 140 ]. Epileptic patients have been reported to have high levels of IL-1ß, IL-1 receptors (IL-1Rs), IL-8, IL-12, MIP-1b, translocator protein (TSPO), toll-like receptor-4 (TLR4), high mobility group box 1 (HMGB1), TNF-α, and cytokine-related genes [ 15 , 47 , 89 , 139 , 140 ]. IL-1ß and TNF-α are the most widely studied, and the concentration of these cytokines is known to be important for protogenic status and inhibition of seizures [ 48 ].…”

“…In this Lafora disease (LD) rodent model, upregulated inflammatory-related genes have been reported through RNA-sequencing ( Table 3 ). Approximately 60% of the upregulated proteins were found to be related to microglia [ 89 ]. LD is a genetically induced epilepsy.…”