Structural and Functional Brain Abnormalities in Mouse Models of Lafora Disease

Abstract

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a−/− mice revealed abnormal glucose uptake, although no alterations in Epm2b−/− mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models.

Polyglucosan body disease in an aged chimpanzee (Pan troglodytes)

“…), the molecular basis of this phenomenon remains uncertain. Studies in genetically modified mouse models are beginning to address such mechanistic questions, at least with regard to inherited versions of PGB disease 55–61 . These models also have helped to advance therapeutic strategies for PGB diseases 62–68 …”

“…Studies in genetically modified mouse models are beginning to address such mechanistic questions, at least with regard to inherited versions of PGB disease. [55][56][57][58][59][60][61] These models also have helped to advance therapeutic strategies for PGB diseases. [62][63][64][65][66][67][68] PGBs with morphologic and distributional characteristics typical of corpora amylacea were present in the hippocampal formation of the chimpanzee, and only sparse PGBs were detected in the neocortex.…”

High‐resolution magic angle spinning NMR for intact biological specimen analysis: Initial discovery, recent developments, and future directions

“…Based on our survey, during 2016-2020, on average, 18.6 publications specified metabolomics as the study target, representing a 38.8% increase from the annual average of 13.4 publications from 2011 to 2015. Similarly, in the past 5 years, on average, more than four reports combined HRMAS NMR with measurements of other methodologies, including mass spectroscopy, [28][29][30][31][32][33][34][35][36][37] microarrays, [38][39][40] immunoassays, 41 genomics, [42][43][44][45][46][47] and the imaging of positron emission tomography (PET) 48,49 and diffusion tensor imaging (DTI). 50 By contrast, from 2011 to 2015, our review found only one such study reported; it combined HRMAS NMR with mass spectroscopy in 2013.…”

“…HRMAS NMR studies involving a variety of animal models of human diseases have been reported in recent publications. The utilized species have included rat, 35,42,55,90,94,[96][97][98][99][100][101][102][103] mouse, 29,48,50,[104][105][106][107][108][109][110][111][112][113][114][115][116] zebrafish, 34,117,118 sheep, 119,120 swine, 121,122 dog, 123 and chicken. 124 In addition to tumors, commonly the subject of HRMAS NMR publications, findings in disease models such as Alzheimer's disease, 105,113 heart transplantation, 99 obesity, 50 and stress, 101,102,110 have been reported.…”