Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice
Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice
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DOI：
10.1093/hmg/11.11.1251
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发表时间：
2002-05-15
影响因子：
3.5
通讯作者：
Yamakawa, K
中科院分区：
文献类型：
--
作者：
Ganesh, S;Delgado-Escueta, AV;Yamakawa, K
编码双特异性磷酸酶（laforin）的EPM2A基因突变导致Lafora病（LD），一种伴有中枢神经系统周期性酸希夫阳性（PAS+）细胞质包涵体（Lafora小体）的进行性和不可避免的致死性癫痫。为了研究LD的病理变化和laforin的功能，我们破坏了小鼠Epm2a基因。在两个月大时，纯合的零突变体发生了广泛的神经元变性，其中大多数发生在缺乏拉福拉体的情况下。在没有凋亡小体或DNA断裂的情况下，濒死神经元的特征表现为内质网、高尔基网和线粒体的肿胀。当拉弗拉体在4-12个月时变得更加突出时，细胞器和细胞核被破坏。Lafora小体存在于神经元和非神经组织中，泛素和晚期糖基化终产物仅在神经元中呈阳性，这表明神经元组织中Lafora包涵体的病理后果不同。神经元变性和拉福拉包涵体早于行为反应受损、共济失调、自发性肌阵挛性发作和脑电图癫痫样活动的发生。我们的研究结果表明，LD是一种原发性神经退行性疾病，可能利用细胞死亡的非凋亡机制。
Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid-Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4-12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.