Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice.
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.
Ganesh
Subramaniam
S
Laboratory for Neurogenetics, RIKEN Brain Science Institute, Wako-shi, Saitama, Japan.
Delgado-Escueta
Antonio V
AV
Sakamoto
Toshiro
T
Avila
Maria Rosa
MR
Machado-Salas
Jesus
J
Hoshii
Yoshinobu
Y
Akagi
Takumi
T
Gomi
Hiroshi
H
Suzuki
Toshimitsu
T
Amano
Kenji
K
Agarwala
Kishan Lal
KL
Hasegawa
Yuki
Y
Bai
Dong-Sheng
DS
Ishihara
Tokuhiro
T
Hashikawa
Tsutomu
T
Itohara
Shigeyoshi
S
Cornford
Eain M
EM
Niki
Hiroaki
H
Yamakawa
Kazuhiro
K
D000818:Animals; D001259:Ataxia / Q000503:physiopathology; D001522:Behavior, Animal; D016923:Cell Death; D054637:Dual-Specificity Phosphatases; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic / Q000503:physiopathology; D005260:Female; D002479:Inclusion Bodies / Q000378:metabolism; D020192:Lafora Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D054637:Dual-Specificity Phosphatases; C491989:Epm2a protein, mouse; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor