Autophagy in spinal motor neurons of conditional ADAR2-knockout mice: An implication for a role of calcium in increased autophagy flux in ALS

•Failure of GluA2 RNA editing resulting from ADAR2 down-regulation occurs in ALS.•Conditional ADAR2-knockout mice are the mechanistic model mice for sporadic ALS.•ADAR2-knockout mice show Ca2+-permeable AMPA receptor-mediated motor neuron death.•Increased autophagy flux is observed in the motor neur...

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Veröffentlicht in:Neuroscience letters 2015-06, Vol.598, p.79-84
Hauptverfasser: Sasaki, Soichi, Yamashita, Takenari, Shin, Kwak
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Sprache:eng
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Zusammenfassung:•Failure of GluA2 RNA editing resulting from ADAR2 down-regulation occurs in ALS.•Conditional ADAR2-knockout mice are the mechanistic model mice for sporadic ALS.•ADAR2-knockout mice show Ca2+-permeable AMPA receptor-mediated motor neuron death.•Increased autophagy flux is observed in the motor neurons of ADAR2-knockout mice.•Abnormally Ca2+-permeable AMPA receptor play roles in autophagy in ALS. In the motor neurons of amyotrophic lateral sclerosis (ALS) patients, an RNA editing enzyme called adenosine deaminase acting on RNA 2 (ADAR2) is down-regulated and consequently GluA2 mRNAs unedited at the Q/R site is expressed in contrast to normal motor neurons that express only GluA2 edited at this site. Motor neurons of the mice lacking ADAR2 undergo Ca2+-permeable AMPA receptor-mediated slow death. We investigated the spinal cords of conditional ADAR2-knockout mice modeling ALS for the involvement of autophagy. In the motor neurons of the early- and late-symptomatic-stage mice, LC3-immunopositivity or immunoreactivity for both LC3- and p62 was observed, whereas the presymptomatic-stage mice showed no LC3- or p62-immunoreactivity. Western blot analyses showed increased expression of autophagy associated proteins in the anterior horn of the early symptomatic-stage mice. Electron-microscopically, autophagy was observed in the motor neurons most frequently in the early-symptomatic-stage mice which showed the severest motor neuron degeneration. Increased autophagy flux was not recognized in the wild-type mice or AR2res (ADAR2flox/flox/VAChT-Cre. Fast/GluR-BR/R) mice having motor neurons genetically engineered to express normally edited GluA2 in the absence of ADAR2, which show normal Ca2+-permeability of the AMPA receptors in motor neurons. Significantly increased autophagy flux in the degenerating motor neurons of ADAR2-knockout mice likely resulted from Ca2+ overload.
ISSN:0304-3940
1872-7972
DOI:10.1016/j.neulet.2015.05.025