Journal Article

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

Olga Criado, Carmen Aguado, Javier Gayarre, Lara Duran-Trio, Ana M. Garcia-Cabrero, Santiago Vernia, Beatriz San Millán, Miguel Heredia, Carlos Romá-Mateo, Silvana Mouron, Lucía Juana-López, Mercedes Domínguez, Carmen Navarro, Jose M. Serratosa, Marina Sanchez, Pascual Sanz, Paola Bovolenta, Erwin Knecht and Santiago Rodriguez de Cordoba

in Human Molecular Genetics

Volume 21, issue 7, pages 1521-1533
Published in print April 2012 | ISSN: 0964-6906
Published online December 2011 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddr590
Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy

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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.

Journal Article.  7220 words.  Illustrated.

Subjects: Genetics and Genomics

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