Human Molecular Genetics, 2002, Vol. 11, No. 11 1251-1262
© 2002 Oxford University Press
Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice
1Laboratory for Neurogenetics, 2Laboratory for Neurobiology of Emotion, 3Laboratory for Neural Architecture and 4Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan, 5Departamento de Neurociencias, Universidad Nacional Autónoma de México, Mexico, 6First Department of Pathology, Yamaguchi University School of Medicine, Yamaguchi, Japan, and 7Epilepsy Genetics/Genomics Laboratories and Comprehensive Epilepsy Program, UCLA School of Medicine and VA GLAHS West Los Angeles Medical Center, Los Angeles, CA, USA
Received January 16, 2002; Accepted March 19, 2002
Mutations in the EPM2A gene encoding a dual-specificity phosphatase (laforin) cause Lafora disease (LD), a progressive and invariably fatal epilepsy with periodic acid–Schiff-positive (PAS+) cytoplasmic inclusions (Lafora bodies) in the central nervous system. To study the pathology of LD and the functions of laforin, we disrupted the Epm2a gene in mice. At two months of age, homozygous null mutants developed widespread degeneration of neurons, most of which occurred in the absence of Lafora bodies. Dying neurons characteristically exhibit swelling in the endoplasmic reticulum, Golgi networks and mitochondria in the absence of apoptotic bodies or fragmentation of DNA. As Lafora bodies become more prominent at 4–12 months, organelles and nuclei are disrupted. The Lafora bodies, present both in neuronal and non-neural tissues, are positive for ubiquitin and advanced glycation end-products only in neurons, suggesting different pathological consequence for Lafora inclusions in neuronal tissues. Neuronal degeneration and Lafora inclusion bodies predate the onset of impaired behavioral responses, ataxia, spontaneous myoclonic seizures and EEG epileptiform activity. Our results suggest that LD is a primary neurodegenerative disorder that may utilize a non-apoptotic mechanism of cell death.
* To whom correspondence should be addressed at: Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel: +81 48 467 9703, Fax: +81 48 467 7095; Email: yamakawa{at}brain.riken.go.jp
Correspondence may also be addressed to: Antonio V. Delgado-Escueta, MD, Epilepsy Genetics/Genomics Laboratories, Comprehensive Epilepsy Program, VA GLAHC Medical Center, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA. Tel: +1 310 268 3129; Fax: +1 310 268 4937; Email: escueta{at}ucla.edu
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