Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.
Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain.
Mol Neurobiol. 2022 Feb;59(2):1214-1229. doi: 10.1007/s12035-021-02682-6. Epub 2021 Dec 28.
Lafora disease (LD) is a fatal childhood-onset dementia characterized by the extensive accumulation of glycogen aggregates-the so-called Lafora Bodies (LBs)-in several organs. The accumulation of LBs in the brain underlies the neurological phenotype of the disease. LBs are composed of abnormal glycogen and various associated proteins, including p62, an autophagy adaptor that participates in the aggregation and clearance of misfolded proteins. To study the role of p62 in the formation of LBs and its participation in the pathology of LD, we generated a mouse model of the disease (malin) lacking p62. Deletion of p62 prevented LB accumulation in skeletal muscle and cardiac tissue. In the brain, the absence of p62 altered LB morphology and increased susceptibility to epilepsy. These results demonstrate that p62 participates in the formation of LBs and suggest that the sequestration of abnormal glycogen into LBs is a protective mechanism through which it reduces the deleterious consequences of its accumulation in the brain.
拉福拉病（LD）是一种致命的儿童期发病的痴呆症，其特征是在多个器官中广泛积累糖原聚集体 - 所谓的拉福拉体（LBs）。 LBs 在大脑中的积累是该疾病神经表型的基础。 LBs 由异常糖原和各种相关蛋白组成，包括 p62，p62 是一种自噬衔接蛋白，参与错误折叠蛋白的聚集和清除。为了研究 p62 在 LBs 形成中的作用及其在 LD 病理学中的参与，我们生成了一种缺乏 p62 的疾病小鼠模型（malin）。 p62 的缺失可防止骨骼肌和心肌组织中 LBs 的积累。在大脑中，p62 的缺失改变了 LB 的形态并增加了癫痫易感性。这些结果表明 p62 参与了 LBs 的形成，并表明将异常糖原隔离到 LBs 中是一种保护机制，通过该机制减轻了其在大脑中积累的有害后果。
