Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy

• Published in: Human molecular genetics Vol. 21; no. 7; pp. 1521 - 1533
• Main Authors: Criado, Olga, Aguado, Carmen, Gayarre, Javier, Duran-Trio, Lara, Garcia-Cabrero, Ana M., Vernia, Santiago, San Millán, Beatriz, Heredia, Miguel, Romá-Mateo, Carlos, Mouron, Silvana, Juana-López, Lucía, Domínguez, Mercedes, Navarro, Carmen, Serratosa, Jose M., Sanchez, Marina, Sanz, Pascual, Bovolenta, Paola, Knecht, Erwin, Rodriguez de Cordoba, Santiago
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2012
• Subjects: Age; Animal models; Animals; Autophagy; Behavior, Animal; Biological and medical sciences; Brain - metabolism; Brain - pathology; Cerebellum; Cortex; Data processing; Dephosphorylation; Dual-Specificity Phosphatases - analysis; Dual-Specificity Phosphatases - metabolism; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Glucans - chemistry; Glycogen; Hippocampus; Lafora Disease - genetics; Lafora Disease - pathology; Lafora Disease - physiopathology; Mice; Mice, Knockout; Molecular and cellular biology; Motor Skills Disorders - genetics; Mutation; Myocardium - ultrastructure; Neurodegenerative diseases; Phagocytosis; Proteolysis; Ubiquitin - analysis; Ubiquitin-Protein Ligases - deficiency; Ubiquitin-Protein Ligases - genetics; Vertebrata; Mammalia; Mouse; Animal; Rodentia; Lafora body; Genetics; Nervous system; Autophagy
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr590

Lafora disease (LD), a fatal neurodegenerative disorder characterized by the presence of intracellular inclusions called Lafora bodies (LBs), is caused by loss-of-function mutations in laforin or malin. Previous studies suggested a role of these proteins in the regulation of glycogen biosynthesis, in glycogen dephosphorylation and in the modulation of the intracellular proteolytic systems. However, the contribution of each of these processes to LD pathogenesis is unclear. We have generated a malin-deficient (Epm2b−/−) mouse with a phenotype similar to that of LD patients. By 3-6 months of age, Epm2b−/− mice present neurological and behavioral abnormalities that correlate with a massive presence of LBs in the cortex, hippocampus and cerebellum. Sixteen-day-old Epm2b−/− mice, without detectable LBs, show an impairment of macroautophagy (hereafter called autophagy), which remains compromised in adult animals. These data demonstrate similarities between the Epm2a−/− and Epm2b−/− mice that provide further insights into LD pathogenesis. They illustrate that the dysfunction of autophagy is a consequence of the lack of laforin-malin complexes and a common feature of both mouse models of LD. Because this dysfunction precedes other pathological manifestations, we propose that decreased autophagy plays a primary role in the formation of LBs and it is critical in LD pathogenesis.