Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India.
Hum Mol Genet. 2017 Dec 15;26(24):4778-4785. doi: 10.1093/hmg/ddx357.
Lafora disease (LD) represents a fatal form of neurodegenerative disorder characterized by the presence of abnormally large number of polyglucosan bodies-called the Lafora bodies-in neurons and other tissues of the affected patients. The disease is caused by defects in the EPM2A gene coding for a protein phosphatase (laforin) or the NHLRC1 gene coding for an ubiquitin ligase (malin). Studies have shown that inhibition of glycogen synthesis in the brain could prevent the formation of Lafora bodies in the neurons and reduce seizure susceptibility in laforin-deficient mouse, an established animal model for LD. Since increased glucose uptake is thought to underlie increased glycogen in LD, and since the adipocyte hormone leptin is known to positively regulate the glucose uptake in neurons, we reasoned that blocking leptin signaling might reduce the neuronal glucose uptake and ameliorate the LD pathology. We demonstrate here that mice that were deficient for both laforin and leptin receptor showed a reduction in the glycogen level, Lafora bodies and gliosis in the brain, and displayed reduced susceptibility to induced seizures as compared to animals that were deficient only for laforin. Thus, blocking leptin signaling could be a one of the effective therapeutic strategies in LD.
拉佛拉病（LD）是一种致命的神经退行性疾病，其特征是神经元和受影响患者的其他组织中存在异常大量的多聚糖体——称为拉佛拉体。该疾病是由编码蛋白磷酸酶（拉佛林）的 EPM2A 基因或编码泛素连接酶（马拉林）的 NHLRC1 基因缺陷引起的。研究表明，抑制大脑中的糖原合成可以防止神经元中拉佛拉体的形成，并降低缺乏拉佛林的小鼠（LD 的一种既定动物模型）的癫痫易感性。由于人们认为 LD 中糖原的增加是由于葡萄糖摄取增加所致，并且已知脂肪细胞激素瘦素可正向调节神经元中的葡萄糖摄取，因此我们推断阻断瘦素信号可能会减少神经元的葡萄糖摄取并改善 LD 病理。我们在这里证明，与仅缺乏拉佛林的动物相比，缺乏拉佛林和瘦素受体的小鼠大脑中的糖原水平、拉佛拉体和神经胶质增生减少，并且对诱导性癫痫的敏感性降低。因此，阻断瘦素信号可能是 LD 的一种有效治疗策略。
