Laforin, the most common protein mutated in Lafora disease, regulates autophagy

10 páginas, 7 figuras.-- This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License.-- et al.Lafora disease (LD) is an autosomal recessive, progressive myoclonus epilepsy, which is characterized by the accumulation of polyglucosan inclusion bodies, called Lafora bodies, in the cytoplasm of cells in the central nervous system and in many other organs. However, it is unclear at the moment whether Lafora bodies are the cause of the disease, or whether they are secondary consequences of a primary metabolic alteration. Here we describe that the major genetic lesion that causes LD, loss-of-function of the protein laforin, impairs autophagy. This phenomenon is confirmed in cell lines from human patients, mouse embryonic fibroblasts from laforin knockout mice and in tissues from such mice. Conversely, laforin expression stimulates autophagy. Laforin regulates autophagy via the mammalian target of rapamycin kinase-dependent pathway. The changes in autophagy mediated by laforin regulate the accumulation of diverse autophagy substrates and would be predicted to impact on the Lafora body accumulation and the cell stress seen in this disease that may eventually contribute to cell death.Work in E.K.’s laboratory was supported by grants from the Spanish Ministry of Science and Innovation (BFU2008- 00186BMC) and the Instituto de Salud Carlos III (Intramural Project, CIBERER). We are also grateful for Hughes Hall Research Fellowship (S.S. and V.I.K.), Wellcome Trust Senior Fellowship in Clinical Science (D.C.R.), Medical Research Council, EU Framework VI (EUROSCA) and the National Institute for Health Research Biomedical Research Centre at Addenbrooke’s Hospital for funding. Funding to pay the Open Access Charge was provided by The Wellcome Trust.Peer reviewe