Unique nuclear vacuoles in the motor neurons of conditional ADAR2-knockout mice.
A reduction in adenosine deaminase acting on RNA 2 (ADAR2) activity causes the death of spinal motor neurons specifically via the GluA2 Q/R site-RNA editing failure in sporadic amyotrophic lateral sclerosis (ALS). We studied, over time, the spinal cords of ADAR2-knockout mice, which are the mechanistic model mice for sporadic ALS, using homozygous ADAR2(flox/flox)/VAChT-Cre.Fast (AR2), homozygous ADAR2(flox/flox)/VAChT-Cre.Slow (AR2Slow), and heterozygous ADAR2(flox/+)/VAChT-Cre.Fast (AR2H) mice. The conditional ADAR2-knockout mice were divided into 3 groups by stage: presymptomatic (AR2H mice), early symptomatic (AR2 mice, AR2H mice) and late symptomatic (AR2Slow mice). Light-microscopically, some motor neurons in AR2 and AR2H mice (presymptomatic) showed simple neuronal atrophy and astrogliosis, and AR2H (early symptomatic) and AR2Slow mice often showed vacuoles predominantly in motor neurons. The number of vacuole-bearing anterior horn neurons decreased with the loss of anterior horn neurons in AR2H mice after 40 weeks of age. Electron-microscopically, in AR2 mice, while the cytoplasm of normal-looking motor neurons was almost always normal-appearing, the interior of dendrites was frequently loose and disorganized. In AR2H and AR2Slow mice, large vacuoles without a limiting membrane were observed in the anterior horns, preferentially in the nuclei of motor neurons, astrocytes and oligodendrocytes. Nuclear vacuoles were not observed in AR2res (ADAR2(flox/flox)/VAChT-Cre.Fast/GluR-B(R/R)) mice, in which motor neurons express edited GluA2 in the absence of ADAR2. These findings suggest that ADAR2-reduction is associated with progressive deterioration of nuclear architecture, resulting in vacuolated nuclei due to a Ca(2+)-permeable AMPA receptor-mediated mechanism.
Department of Neurology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Electronic address: ssasaki@nij.twmu.ac.jp.
Shoichi
S
Sasaki
Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan; Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Japan.
Takenari Yamashita
Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan.
Takuto
T
Hideyama
Department of Neurology, Graduate School of Medicine, University of Tokyo, Japan; Division of Clinical Biotechnology, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Japan; Clinical Research Center for Medicine, International University of Health and Welfare, Japan.
Shin
S
Kwak
D000243:Adenosine Deaminase / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D000870:Anterior Horn Cells / Q000648:ultrastructure; D001253:Astrocytes / Q000473:pathology; D001284:Atrophy; D002452:Cell Count; D002467:Cell Nucleus / Q000648:ultrastructure*; D003593:Cytoplasm / Q000648:ultrastructure; D003712:Dendrites / Q000648:ultrastructure; D018450:Disease Progression; D005911:Gliosis / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000648:ultrastructure*; D016601:RNA-Binding Proteins; D013045:Species Specificity; D013116:Spinal Cord / Q000648:ultrastructure*; D014617:Vacuoles / Q000648:ultrastructure*
D016601:RNA-Binding Proteins; C567955:ADARB1 protein, human; D000243:Adenosine Deaminase
AMPA receptor; Amyotrophic lateral sclerosis; Conditional ADAR2-knockout mouse; Electron microscopy; GluA2; Motor neuron disease; Nuclear vacuole; Pathology; RNA editing