Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease

Abstract

BackgroundLafora 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.ResultsIn 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.ConclusionsHere, 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.

Pathway-driven discovery of epilepsy genes

“…A third wave of genes achieving prominence includes those found in syndromic epilepsies composed of purely neurological but seemingly unrelated comorbidities, such autism 33,34 , familial Alzheimer’s disease 35,36 , cognitive disorders 9,37 , dyskinesias 38 , migraine 39 and ataxias 40,41 , illustrating how a seizure disorder can appear alongside or in the wake of another neurological deficit during its neurodegenerative trajectory. The genetic overlap with autism is particularly notable 42 .…”

Long-term exposure to 835 MHz RF-EMF induces hyperactivity, autophagy and demyelination in the cortical neurons of mice

“…It is a highly-developed region of the human brain that processes most of the actual information, including sensory functions, such as hearing, touch, vision, smell, and movement, as well as cognitive functions, such as thought, perception, memory-related problem solving, and understanding language2425. Abnormalities of the human cerebral cortical region could be associated with various neurodegenerative diseases including Alzheimer’s disease, Lafora disease, and various cognitive disorders262728. RF-EMF exposure of the human cerebral cortex reportedly causes physiological alterations in blood flow and increases glucose metabolism2930.…”

Lafora Disease: A Case Report

“…[19] Bu hipotezi doğrulayabilecek bazı bilgilerse, yakın zamanda yapılan ilaç çalışmalarında kısmen göste-rilmiştir. Selektif, non-kompetetif AMPA tipi glutamat reseptör antagonisti olan perampanelin kullanıldığı sınırlı sayıdaki olguda, ilacın etkinliği sadece nöbet sıklığında azalma ile değil, nörokognitif ve serebellar disfonksiyondaki iyileşme şeklinde tanımlanmıştır.…”