Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Saida
S
Ortolano
Irene
I
Vieitez
Roberto Carlos
RC
Agis-Balboa
Group of Neurodegenerative Diseases and Psychiatric Disorders, Institute of Biomedical Research of Vigo (IBIV), Xerencia de Xestion Integrada de Vigo, SERGAS, Psychiatric Hospital Rebullón, Puxeiros s/n, Pontevedra 36415 Mos, Spain. carlos.spuch@gmail.com.
Carlos
C
Spuch
D000199:Actins / Q000378:metabolism; D000375:Aging / Q000473:pathology; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D002467:Cell Nucleus / Q000378:metabolism; D002540:Cerebral Cortex / Q000473:pathology*; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D054637:Dual-Specificity Phosphatases / Q000172:deficiency / Q000378:metabolism; D059330:GABAergic Neurons / Q000201:enzymology / Q000473:pathology*; D002479:Inclusion Bodies / Q000378:metabolism; D020192:Lafora Disease / Q000473:pathology*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D021381:Protein Transport; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D059748:Proteolysis; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000199:Actins; D009414:Nerve Growth Factors; D016159:Tumor Suppressor Protein p53; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D053148:Caspase 3