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

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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 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.

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Abbreviations

FC:

Fold change

FDR:

False discovery rate

LD:

Lafora disease

RT-qPCR:

Real-time quantitative polymerase chain reaction

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Acknowledgments

We want to thank Miguel Heredia (CIBERER) for his help in obtaining the brain samples and Ursula Estada (Multigenic Analysis Unit from the UCIM-INCLIVA; University of Valencia, Valencia, Spain) for her help in constructing libraries and performing RNA-Seq experiments.

Funding

This work was supported by grants from the Spanish Ministry of Economy and Competitiveness SAF2014-54604-C3-1-R and SAF2017-83151-R, a grant from Fundación Ramón Areces (CIVP18A3935), and a grant from the National Institute of Health (NIH-NINDS) P01NS097197, which established the Lafora Epilepsy Cure Initiative (LECI), to PS. We also acknowledge a grant from the Spanish Ministry of Economy and Competitiveness SAF2014-54604-C3-2-R to EK and a grant from Generalitat Valenciana Prometeo2018/135 to PS and FVP.

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Authors and Affiliations

  1. Consejo Superior de Investigaciones Científicas, Instituto de Biomedicina de Valencia, Jaime Roig 11, 46010, Valencia, Spain

    Marcos Lahuerta, Mireia Moreno-Estellés & Pascual Sanz

  2. EpiDisease S.L. (Spin-Off from the CIBER-ISCIII), Parc Científic de la Universitat de València, Paterna, Spain

    Daymé Gonzalez & José Luis García-Giménez

  3. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain

    Carmen Aguado, Alihamze Fathinajafabadi, José Luis García-Giménez, Carlos Romá-Mateo, Erwin Knecht, Federico V. Pallardó & Pascual Sanz

  4. Centro de Investigación Príncipe Felipe, Valencia, Spain

    Carmen Aguado, Alihamze Fathinajafabadi & Erwin Knecht

  5. Dept. Fisiología, Facultad de Medicina y Odontología, Universidad de Valencia-INCLIVA, Valencia, Spain

    José Luis García-Giménez, Carlos Romá-Mateo & Federico V. Pallardó

Authors
  1. Marcos Lahuerta
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  2. Daymé Gonzalez
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  3. Carmen Aguado
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Contributions

ML, CA, and AF prepared the samples for RNA-Seq and performed the RT-qPCR; ML and MM-E conducted the western blot analyses; MM-E carried out the immunofluorescence analyses; DG and JLG-G performed the bioinformatics analyses; ML, MM-E, and CR-M analyzed the data; and EK, FVP, and PS interpreted the data and wrote the manuscript.

Corresponding author

Correspondence to Pascual Sanz.

Ethics declarations

This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the Consejo Superior de Investigaciones Cientificas (CSIC, Spain) and approved by the Consellería de Agricultura, Medio Ambiente, Cambio Climático y Desarrollo Rural from the Generalitat Valenciana. All mouse procedures were approved by the animal committee of the Instituto de Biomedicina de Valencia-CSIC [Permit Number: (IBV-16), 2015/VSC/PEA/00029].

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The authors declare that they have no conflict of interest.

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Marcos Lahuerta and Daymé Gonzalez should be regarded as joint first authors.

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Lahuerta, M., Gonzalez, D., Aguado, C. et al. Reactive Glia-Derived Neuroinflammation: a Novel Hallmark in Lafora Progressive Myoclonus Epilepsy That Progresses with Age. Mol Neurobiol 57, 1607–1621 (2020). https://doi.org/10.1007/s12035-019-01842-z

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