EPM2A
Laforin (EC 3.1.3.-) (EC 3.1.3.16) (EC 3.1.3.48) (Glucan phosphatase) (Glycogen phosphatase) (Lafora PTPase) (LAFPTPase)
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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.
MeSH Terms
- Aging
- Animals
- Astrocytes
- Biomarkers
- Calcium-Binding Proteins
- Cyclooxygenase 2
- Cytokines
- Disease Models, Animal
- Disease Progression
- Dual-Specificity Phosphatases
- Gene Expression Regulation
- Glial Fibrillary Acidic Protein
- Hippocampus
- Inclusion Bodies
- Inflammation
- Inflammation Mediators
- Lafora Disease
- Mice, Inbred C57BL
- Mice, Knockout
- Microfilament Proteins
- Microglia
- Protein Tyrosine Phosphatases, Non-Receptor
- RNA, Messenger
- Telencephalon
- Ubiquitin-Protein Ligases
Keywords
- Chemokines
- Cytokines
- Inflammation
- Lafora disease
- Microglia
- Polyglucosan
Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the [[EPM2A]] and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the [[EPM2A]] gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes. However, the pathogenesis and the molecular mechanism of the disease, which imply either laforin or malin are poorly understood. Thus, the aim of our study is to elucidate the molecular mechanism of the pathology by characterizing cerebral cortex neurodegeneration in the well accepted murine model of Lafora disease [[EPM2A]]-/- mouse. In this article, we want to asses the primary cause of the neurodegeneration in Lafora disease by studying GABAergic neurons in the cerebral cortex. We showed that the majority of Lafora bodies are specifically located in GABAergic neurons of the cerebral cortex of 3 months-old [[EPM2A]]-/- mice. Moreover, GABAergic neurons in the cerebral cortex of younger mice (1 month-old) are decreased in number and present altered neurotrophins and p75NTR signalling. Here, we concluded that there is impairment in GABAergic neurons neurodevelopment in the cerebral cortex, which occurs prior to the formation of Lafora bodies in the cytoplasm. The dysregulation of cerebral cortex development may contribute to Lafora disease pathogenesis.
MeSH Terms
- Actins
- Aging
- Animals
- Caspase 3
- Cell Count
- Cell Nucleus
- Cerebral Cortex
- Dendrites
- Dual-Specificity Phosphatases
- GABAergic Neurons
- Inclusion Bodies
- Lafora Disease
- Lysosomes
- Mice
- Nerve Growth Factors
- Protein Transport
- Protein Tyrosine Phosphatases, Non-Receptor
- Proteolysis
- Subcellular Fractions
- Synapses
- Tumor Suppressor Protein p53
Lafora's disease, an autosomal recessive progressive myoclonus epilepsy, is caused by mutations in the [[EPM2A]] gene encoding a dual-specificity phosphatase (DSP) named laforin. Here, we analyzed the developmental and regional expression of murine Epm2a and discussed its evolutionary conservation. A phylogenetic analysis indicated that laforin is evolutionarily distant from other DSPs. Southern zoo blot analysis suggested that conservation of Epm2a gene is limited to mammals. Laforin orthologs (human, mouse, and rat) display more than 94% similarity. All missense mutations known in Lafora disease patients affect conserved residues, suggesting that they may be essential for laforin's function. Epm2a is expressed widely in various organs but not homogeneously in brain. The levels of Epm2a transcripts in mice brains increase postnatally, attaining its highest level in adults. The most intense signal was detected in the cerebellum, hippocampus, cerebral cortex, and the olfactory bulb. Our results suggest that Epm2a is functionally conserved in mammals and is involved in growth and maturation of neural networks.
MeSH Terms
- Aging
- Amino Acid Sequence
- Amino Acid Substitution
- Animals
- Brain
- Cerebral Cortex
- Conserved Sequence
- Dual-Specificity Phosphatases
- Embryonic and Fetal Development
- Evolution, Molecular
- Gene Expression Regulation, Developmental
- Gene Library
- Humans
- In Situ Hybridization, Fluorescence
- Male
- Mice
- Molecular Sequence Data
- Mutation, Missense
- Organ Specificity
- Phylogeny
- Protein Tyrosine Phosphatases
- Protein Tyrosine Phosphatases, Non-Receptor
- Rats
- Sequence Alignment
- Sequence Homology, Amino Acid
- Vertebrates