Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease.
Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease.
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DOI：
10.1007/s12035-015-9091-8
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发表时间：
2016-03
影响因子：
5.1
通讯作者：
Sanz P
中科院分区：
文献类型：
--
作者：
Berthier A;Payá M;García-Cabrero AM;Ballester MI;Heredia M;Serratosa JM;Sánchez MP;Sanz P
Lafora病（LD，OMIM 254780）是一种罕见的致命性神经退行性疾病，通常发生在儿童时期，伴有全身强直阵挛性癫痫发作、肌阵挛、失神、跌倒发作或视觉癫痫发作。不幸的是，目前可用的治疗方法只是治标不治本，还没有治疗药物。这种疾病的标志是不溶性葡聚糖内含物的积累，称为Lafora小体（LB），在神经元内，但也在心脏，肌肉和肝细胞中。缺乏功能性EPM2A或EPM2B基因（与疾病相关的两个主要基因座）的小鼠模型重现了Lafora疾病表型：它们积累葡聚糖内含物，显示神经变性的迹象，并具有蛋白质清除和内质网应激反应的失调。在这项研究中，我们对LD（Epm2b −/−）小鼠模型进行了不同的药物干预，旨在减轻蛋白质清除和内质网应激。我们使用了两种化学伴侣，海藻糖和4-苯基丁酸。此外，我们还使用了二甲双胍，一种AMP活化蛋白激酶（AMPK）的激活剂，因为它在其他神经退行性疾病中具有公认的神经保护作用。在这里，我们表明，用4-苯基丁酸或二甲双胍治疗减少了Lafora小体和多聚泛素蛋白聚集体在治疗动物脑中的积累。4-苯丁酸和二甲双胍还可以减轻神经退行性变（以神经元丢失和反应性神经胶质增生来衡量），并改善Epm 2b-/-小鼠的神经心理学测试。由于这些化合物具有良好的安全记录，并且已经被批准用于不同神经病理学的临床用途，我们认为将我们的结果转化为临床实践可能是简单的。
Lafora disease (LD, OMIM 254780) is a rare fatal neurodegenerative disorder that usually occurs during childhood with generalized tonic-clonic seizures, myoclonus, absences, drop attacks or visual seizures. Unfortunately, at present, available treatments are only palliatives and no curative drugs are available yet. The hallmark of the disease is the accumulation of insoluble polyglucosan inclusions, called Lafora bodies (LBs), within the neurons but also in heart, muscle and liver cells. Mouse models lacking functional EPM2A or EPM2B genes (the two major loci related to the disease) recapitulate the Lafora disease phenotype: they accumulate polyglucosan inclusions, show signs of neurodegeneration and have a dysregulation of protein clearance and endoplasmic reticulum stress response. In this study, we have subjected a mouse model of LD (Epm2b−/−) to different pharmacological interventions aimed to alleviate protein clearance and endoplasmic reticulum stress. We have used two chemical chaperones, trehalose and 4-phenylbutyric acid. In addition, we have used metformin, an activator of AMP-activated protein kinase (AMPK), as it has a recognized neuroprotective role in other neurodegenerative diseases. Here, we show that treatment with 4-phenylbutyric acid or metformin decreases the accumulation of Lafora bodies and polyubiquitin protein aggregates in the brain of treated animals. 4-Phenylbutyric acid and metformin also diminish neurodegeneration (measured in terms of neuronal loss and reactive gliosis) and ameliorate neuropsychological tests of Epm2b−/− mice. As these compounds have good safety records and are already approved for clinical uses on different neurological pathologies, we think that the translation of our results to the clinical practice could be straightforward.