Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain.
Brain. 2021 Sep 4;144(8):2349-2360. doi: 10.1093/brain/awab110.
The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes-thus impeding Lafora bodies accumulation in this cell type-prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.
拉佛拉病是一种致命的神经退行性疾病，其特征是细胞内糖原聚集物（称为拉佛拉体）的积累。直到最近，人们普遍认为脑内拉佛拉体仅存在于神经元中，因此拉佛拉病的病理源自于这些细胞群体中拉佛拉体的积累。然而，最近的证据表明，拉佛拉体也存在于星形胶质细胞中。为了确定星形胶质细胞中拉佛拉体在拉佛拉病病理中的作用，我们在疾病的小鼠模型中特异性地敲除了星形胶质细胞中的糖原合酶（malinKO）。令人惊讶的是，阻断星形胶质细胞中的糖原合成——从而阻止这种细胞类型中拉佛拉体的积累——可防止神经退行性标志物、自噬损伤和代谢变化的增加，这些都是 malinKO 模型的特征。相反，在星形胶质细胞中过度积累糖原的小鼠，这些标志物的水平会增加。这些结果揭示了星形胶质细胞中糖原代谢失调的有害后果，并改变了拉佛拉病仅由神经元改变引起的观点。
