title: Inflammation in Lafora Disease: Evolution with Disease Progression in Laforin and Malin Knock-out Mouse Models.
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.
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patologica, Hospital Universitari de Bellvitge, Carrer Feixa Llarga sn, Hospitalet de Llobregat, 08907, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: López-González
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Jaime Roig 11, 46010, Valencia, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Viana
authors.affiliation: Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas, Jaime Roig 11, 46010, Valencia, Spain. sanz@ibv.csic.es.|CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Institute Carlos III, Madrid, Spain. sanz@ibv.csic.es.
authors.forename: Pascual
authors.initials: P
authors.lastname: Sanz
authors.affiliation: Institut de Neuropatologia, Servei Anatomia Patologica, Hospital Universitari de Bellvitge, Carrer Feixa Llarga sn, Hospitalet de Llobregat, 08907, Barcelona, Spain. 8082ifa@gmail.com.|University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain. 8082ifa@gmail.com.|CIBERNED (Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas), Ministry of Science and Innovation, Institute Carlos III, Madrid, Spain. 8082ifa@gmail.com.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D054637:Dual-Specificity Phosphatases / Q000172:deficiency* / Q000378:metabolism; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D002479:Inclusion Bodies / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D018836:Inflammation Mediators / Q000378:metabolism; D020192:Lafora Disease / Q000473:pathology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013687:Telencephalon / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency* / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D015415:Biomarkers; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D018836:Inflammation Mediators; D008840:Microfilament Proteins; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; C572596:NHLRC1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: Chemokines; Cytokines; Inflammation; Lafora disease; Microglia; Polyglucosan