Laforin, the most common protein mutated in Lafora disease, regulates autophagy.
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.
Aguado
Carmen
C
Laboratory of Cellular Biology, Centro de Investigación Príncipe Felipe and CIBERER, Avda. Autopista del Saler 16, 46012 Valencia, Spain.
Sarkar
Sovan
S
Korolchuk
Viktor I
VI
Criado
Olga
O
Vernia
Santiago
S
Boya
Patricia
P
Sanz
Pascual
P
de Córdoba
Santiago Rodríguez
SR
Knecht
Erwin
E
Rubinsztein
David C
DC
D000818:Animals; D001343:Autophagy / Q000235:genetics*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology; D020192:Lafora Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human
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