Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 88, Issue -, Pages 30-41Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2015.01.034
Keywords
Lafora disease; Oxidative stress; Proteostasis; Laforin; Malin; Free radicals
Funding
- Spanish Ministry of Education and Science [SAF2011-27442, BFU2011-22630]
- Fundacio La Marato de TV3 [100130]
- Generalitat Valenciana [Prometeo 2009/051, Prorneteo 2012/061]
- ACCI2012 action from CIBERER, an initiative of the Instituto de Salud Carlos III
- Saving Lives at Birth Consortium
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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 EPM24 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 detects 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 detects in protein homeostasis present in LD and oxidative stress. (C) 2015 Published by Elsevier Inc.
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