Instituto de Biomedicina de Valencia (IBV-CSIC), 46010 Valencia, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)-ISCIII, 28029 Madrid, Spain.
Int J Mol Sci. 2023 Mar 23;24(7):6020. doi: 10.3390/ijms24076020.
Lafora disease (LD) is a neurological disorder characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of insoluble forms of glycogen (polyglucosan bodies, or PGBs) in the brain. The accumulation of PGBs is causative of the pathophysiological features of LD. However, despite the efforts made by different groups, the question of why PGBs accumulate in the brain is still unanswered. We have recently demonstrated that, in vivo, astrocytes accumulate most of the PGBs present in the brain, and this could lead to astrocyte dysfunction. To develop a deeper understanding of the defects present in LD astrocytes that lead to LD pathophysiology, we obtained pure primary cultures of astrocytes from LD mice from the postnatal stage under conditions that accumulate PGBs, the hallmark of LD. These cells serve as novel in vitro models for studying PGBs accumulation and related LD dysfunctions. In this sense, the metabolomics of LD astrocytes indicate that they accumulate metabolic intermediates of the upper part of the glycolytic pathway, probably as a consequence of enhanced glucose uptake. In addition, we also demonstrate the feasibility of using the model in the identification of different compounds that may reduce the accumulation of polyglucosan inclusions.
拉佛拉病（LD）是一种以进行性肌阵挛癫痫为特征的神经退行性疾病。该疾病的标志是脑内存在不溶性糖原形式（多葡聚糖体，或 PGBs）。PGBs 的积累是 LD 病理生理学特征的原因。然而，尽管不同的研究小组做出了努力，为什么 PGBs 在大脑中积累的问题仍然没有答案。我们最近证明，在体内，星形胶质细胞积累了大脑中存在的大部分 PGBs，这可能导致星形胶质细胞功能障碍。为了更深入地了解导致 LD 病理生理学的 LD 星形胶质细胞中存在的缺陷，我们从 LD 小鼠的出生后阶段获得了在积累 PGBs 的条件下产生的纯原代星形胶质细胞培养物，这是 LD 的标志。这些细胞为研究 PGBs 积累和相关 LD 功能障碍提供了新型的体外模型。从这个意义上说，LD 星形胶质细胞的代谢组学表明，它们积累了糖酵解途径上游的代谢中间产物，可能是由于增强的葡萄糖摄取所致。此外，我们还证明了该模型在鉴定可能减少多葡聚糖包涵体积累的不同化合物方面的可行性。
