Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease.
Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease.
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作者：
Augé E;Pelegrí C;Manich G;Cabezón I;Guinovart JJ;Duran J;Vilaplana J
Lafora病（LD）是最具破坏性的青春期癫痫，是由EPM2A或EPM2B基因突变引起的，这两个基因分别编码laforin和malin蛋白。其中一种蛋白质参与糖原合成的调节，其功能的丧失会诱导多葡聚糖小体（PGBs）的积累，多葡聚糖小体被称为拉弗拉小体（LBs），与大脑中的神经元有关。衰老和一些神经退行性疾病导致另一种类型的PGB出现，称为淀粉样体，它与星形胶质细胞相关，含有可被天然抗体识别的新表位。我们研究了malin基因敲除小鼠（LD小鼠模型）大脑皮层和海马中的PGBs。这些动物不仅存在与神经元相关的LBs，还存在大量与星形胶质细胞相关的PGBs。这些星形细胞PGBs在衰老加速小鼠易感8 （SAMP8）菌株和糖原蛋白（PTGOE）过表达小鼠中也有所增加，表明它们并非LD的专属。星形细胞PGBs含有可被天然抗体识别的新表位，而非神经元LBs。星形细胞PGBs主要出现在海马区，但也存在于一些脑皮质区，而神经元LBs主要存在于脑皮质和海马区CA2和CA3的锥体层。我们的研究结果表明，星形胶质细胞与目前的观点相反，参与了LD的发病机制。
Lafora disease (LD), the most devastating adolescence-onset epilepsy, is caused by mutations in the EPM2A or EPM2B genes, which encode the proteins laforin and malin, respectively. Loss of function of one of these proteins, which are involved in the regulation of glycogen synthesis, induces the accumulation of polyglucosan bodies (PGBs)—known as Lafora bodies (LBs) and associated with neurons—in the brain. Ageing and some neurodegenerative conditions lead to the appearance of another type of PGB called corpora amylacea, which are associated with astrocytes and contain neo-epitopes that can be recognized by natural antibodies. Here we studied the PGBs in the cerebral cortex and hippocampus of malin knockout mice, a mouse model of LD. These animals presented not only LBs associated with neurons but also a significant number of PGBs associated with astrocytes. These astrocytic PGBs were also increased in mice from senescence-accelerated mouse-prone 8 (SAMP8) strain and mice with overexpression of Protein Targeting to Glycogen (PTGOE), indicating that they are not exclusive of LD. The astrocytic PGBs, but not neuronal LBs, contained neo-epitopes that are recognized by natural antibodies. The astrocytic PGBs appeared predominantly in the hippocampus but were also present in some cortical brain regions, while neuronal LBs were found mainly in the brain cortex and the pyramidal layer of hippocampal regions CA2 and CA3. Our results indicate that astrocytes, contrary to current belief, are involved in the etiopathogenesis of LD.
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影响因子：
3.5
作者：
Aguado C;Sarkar S;Korolchuk VI;Criado O;Vernia S;Boya P;Sanz P;de Córdoba SR;Knecht E;Rubinsztein DC
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