Unique nuclear vacuoles in the motor neurons of conditional ADAR2-knockout mice

摘要: A reduction in adenosine deaminase acting on RNA 2 (ADAR2) activity causes the death of spinal motor neurons specifically via GluA2 Q/R site-RNA editing failure sporadic amyotrophic lateral sclerosis (ALS). We studied, over time, cords ADAR2-knockout mice, which are mechanistic model mice for ALS, using homozygous ADAR2(flox/flox)/VAChT-Cre.Fast (AR2), ADAR2(flox/flox)/VAChT-Cre.Slow (AR2Slow), and heterozygous ADAR2(flox/+)/VAChT-Cre.Fast (AR2H) mice. The conditional were divided into 3 groups by stage: presymptomatic (AR2H mice), early symptomatic (AR2 AR2H mice) late (AR2Slow mice). Light-microscopically, some AR2 (presymptomatic) showed simple neuronal atrophy astrogliosis, (early symptomatic) AR2Slow often vacuoles predominantly neurons. number vacuole-bearing anterior horn decreased with loss after 40 weeks age. Electron-microscopically, while cytoplasm normal-looking was almost always normal-appearing, interior dendrites frequently loose disorganized. In large without a limiting membrane observed horns, preferentially nuclei neurons, astrocytes oligodendrocytes. Nuclear not AR2res (ADAR2(flox/flox)/VAChT-Cre.Fast/GluR-B(R/R)) express edited absence ADAR2. These findings suggest that ADAR2-reduction is associated progressive deterioration nuclear architecture, resulting vacuolated due to Ca(2+)-permeable AMPA receptor-mediated mechanism.