Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
Int J Mol Sci. 2022 Jun 20;23(12):6874. doi: 10.3390/ijms23126874.
Mutations in the gene encoding laforin cause Lafora disease (LD), a progressive myoclonic epilepsy characterized by drug-resistant seizures and progressive neurological impairment. To date, rodents are the only available models for studying LD; however, their use for drug screening is limited by regulatory restrictions and high breeding costs. To investigate the role of laforin loss of function in early neurodevelopment, and to screen for possible new compounds for treating the disorder, we developed a zebrafish model of LD. Our results showed the zebrafish to be a faithful model of LD, exhibiting the main disease features, namely motor impairment and neuronal hyperexcitability with spontaneous seizures. The model also showed increased inflammatory response and apoptotic death, as well as an altered autophagy pathway that occurs early in development and likely contributes to the disease progression. Early administration of trehalose was found to be effective for rescuing motor impairment and neuronal hyperexcitability associated with seizures. Our study adds a new tool for investigating LD and might help to identify new treatment opportunities.
Lafora 病（LD）是一种进行性肌阵挛性癫痫，其特征是耐药性癫痫发作和进行性神经功能障碍，导致该疾病的基因突变存在于编码 laforin 的基因中。迄今为止，啮齿动物是研究 LD 的唯一可用模型；然而，由于监管限制和高昂的繁殖成本，它们在药物筛选方面的应用受到限制。为了研究 laforin 功能丧失在早期神经发育中的作用，并筛选可能用于治疗该疾病的新化合物，我们开发了一种 LD 的斑马鱼模型。我们的研究结果表明，斑马鱼是 LD 的忠实模型，表现出主要的疾病特征，即运动障碍和神经元过度兴奋，伴有自发性癫痫发作。该模型还表现出炎症反应和细胞凋亡增加，以及自噬途径的改变，这些改变发生在发育早期，可能导致疾病进展。早期给予海藻糖可有效缓解与癫痫相关的运动障碍和神经元过度兴奋。我们的研究为研究 LD 增加了一个新工具，并可能有助于发现新的治疗机会。
