Fundación Investigación Clinico de Valencia, Instituto de Investigación Sanitaria, Valencia, Spain; Department of Physiology, School of Medicine and Dentistry, University of Valencia, E46010 Valencia, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras, Valencia, Spain; Centro de Investigación Príncipe Felipe, Valencia, Spain.
Free Radic Biol Med. 2015 Nov;88(Pt A):30-41. doi: 10.1016/j.freeradbiomed.2015.01.034. Epub 2015 Feb 10.
Lafora disease (LD; OMIM 254780, ORPHA501) is a devastating neurodegenerative disorder characterized by the presence of glycogen-like intracellular inclusions called Lafora bodies and caused, in most cases, by mutations in either the EPM2A or the EPM2B gene, encoding respectively laforin, a phosphatase with dual specificity that is involved in the dephosphorylation of glycogen, and malin, an E3-ubiquitin ligase involved in the polyubiquitination of proteins related to glycogen metabolism. Thus, it has been reported that laforin and malin form a functional complex that acts as a key regulator of glycogen metabolism and that also plays a crucial role in protein homeostasis (proteostasis). Regarding this last function, it has been shown that cells are more sensitive to ER stress and show defects in proteasome and autophagy activities in the absence of a functional laforin-malin complex. More recently, we have demonstrated that oxidative stress accompanies these proteostasis defects and that various LD models show an increase in reactive oxygen species and oxidative stress products together with a dysregulated antioxidant enzyme expression and activity. In this review we discuss possible connections between the multiple defects in protein homeostasis present in LD and oxidative stress.
拉佛拉病（LD；OMIM 254780，ORPHA501）是一种破坏性的神经退行性疾病，其特征是存在称为拉佛拉体的糖原样细胞内包涵体，并且在大多数情况下是由 EPM2A 或 EPM2B 基因突变引起的，分别编码具有双重特异性的磷酸酶 laforin，其参与糖原的去磷酸化，和 malin，一种 E3-泛素连接酶，参与与糖原代谢相关的蛋白质的多泛素化。因此，据报道，laforin 和 malin 形成一个功能复合物，作为糖原代谢的关键调节剂，并且在蛋白质稳态（proteostasis）中也起着至关重要的作用。关于后一种功能，已经表明在没有功能性 laforin-malin 复合物的情况下，细胞对 ER 应激更敏感，并显示出蛋白酶体和自噬活性的缺陷。最近，我们已经证明氧化应激伴随着这些蛋白质稳态缺陷，并且各种 LD 模型显示活性氧和氧化应激产物增加，以及抗氧化酶表达和活性的失调。在这篇综述中，我们讨论了 LD 中存在的蛋白质稳态的多种缺陷与氧化应激之间可能存在的联系。
