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Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models

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Abstract

Lafora progressive myoclonus epilepsy (Lafora disease, LD) is a fatal rare autosomal recessive neurodegenerative disorder characterized by the accumulation of insoluble ubiquitinated polyglucosan inclusions in the cytoplasm of neurons, which is most commonly associated with mutations in two genes: EPM2A, encoding the glucan phosphatase laforin, and EPM2B, encoding the E3-ubiquitin ligase malin. The present study analyzes possible inflammatory responses in the mouse lines Epm2a −/− (laforin knock-out) and Epm2b −/− (malin knock-out) with disease progression. Increased numbers of reactive astrocytes (expressing the GFAP marker) and microglia (expressing the Iba1 marker) together with increased expression of genes encoding cytokines and mediators of the inflammatory response occur in both mouse lines although with marked genotype differences. C3ar1 and CxCl10 messenger RNAs (mRNAs) are significantly increased in Epm2a −/− mice aged 12 months when compared with age-matched controls, whereas C3ar1, C4b, Ccl4, CxCl10, Il1b, Il6, Tnfα, and Il10ra mRNAs are significantly upregulated in Epm2b −/− at the same age. This is accompanied by increased protein levels of IL1-β, IL6, TNFα, and Cox2 particularly in Epm2b −/− mice. The severity of inflammatory changes correlates with more severe clinical symptoms previously described in Epm2b −/− mice. These findings show for the first time increased innate inflammatory responses in a neurodegenerative disease with polyglucosan intraneuronal deposits which increase with disease progression, in a way similar to what is seen in neurodegenerative diseases with abnormal protein aggregates. These findings also point to the possibility of using anti-inflammatory agents to mitigate the degenerative process in LD.

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Acknowledgements

This study was funded by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III—Fondos FEDER, a way to build Europe FIS grants PI14/00757 and PI14/00328 to IF, and grants from the Spanish Ministry of Economy and Competiveness SAF2014-54604-C3-1-R and from the Generalitat Valenciana (PrometeoII/2014/029) to PS. We thank T. Yohannan for the editorial assistance.

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    Authors and Affiliations

    1. Institut de Neuropatologia, Servei Anatomia Patologica, Hospital Universitari de Bellvitge, Carrer Feixa Llarga sn, Hospitalet de Llobregat, 08907, Barcelona, Spain

      Irene López-González & Isidre Ferrer

    2. University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain

      Isidre Ferrer

    3. CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Ministry of Science and Innovation, Institute Carlos III, Madrid, Spain

      Isidre Ferrer

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

      Rosa Viana & Pascual Sanz

    5. CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Institute Carlos III, Madrid, Spain

      Pascual Sanz

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    1. Irene López-González
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    2. Rosa Viana
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    Correspondence to Pascual Sanz or Isidre Ferrer.

    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). All mouse procedures were approved by the animal committee of the Instituto de Biomedicina de Valencia-CSIC [Permit Number: INTRA12 (IBV-4)]. All efforts were made to minimize animal suffering.

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    Statement of Author Contributions

    I.L.-G. carried out the analysis of gene and protein expression; R.V. did the immunohistochemical study; P.S. and I.F. designed and supervised the work. All authors were involved in writing the paper and had final approval of the submitted and published version.

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    Irene López-González and Rosa Viana contributed equally to this work.

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    López-González, I., Viana, R., Sanz, P. et al. Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models. Mol Neurobiol 54, 3119–3130 (2017). https://doi.org/10.1007/s12035-016-9884-4

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