期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 36, 页码 8830-8844出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0730-17.2017
关键词
animal model; excitotoxicity; glutamate; motor neuron; transporter
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Medical Research Institute (MRI), Tokyo Medical and Dental University (TMDU)
- Nanken-Kyoten, TMDU
- Grants-in-Aid for Scientific Research [17H02216, 15J04805, 16H01383] Funding Source: KAKEN
Glutamate-mediated excitotoxicity induces neuronal death by altering various intracellular signaling pathways and is implicated as a common pathogenic pathway in many neurodegenerative diseases. In the case of motor neuron disease, there is significant evidence to suggest that the overactivation of AMPA receptors due to deficiencies in the expression and function of glial glutamate transporters GLT1 and GLAST plays an important role in the mechanisms of neuronal death. However, a causal role for glial glutamate transporter dysfunction in motor neuron death remains unknown. Here, we developed a new animal model of excitotoxicity by conditionally deleting astroglial glutamate transporters GLT1 and GLAST in the spinal cords of mice (GLAST(+/-)/GLT1-cKO). GLAST(+/-)/GLT1-cKO mice (both sexes) exhibited nuclear irregularity and calpain-mediated degradation of nuclear pore complexes (NPCs), which are responsible for nucleocytoplasmic transport. These abnormalities were associated with progressive motor neuron loss, severe paralysis, and shortened lifespan. The nuclear export inhibitor KPT-350 slowed but did not prevent motor neuron death, whereas long-term treatment of the AMPA receptor antagonist perampanel and the calpain inhibitor SNJ-1945 had more persistent beneficial effects. Thus, NPC degradation contributes to AMPA receptor-mediated excitotoxic motor neuronal death, and preventing NPC degradation has robust protective effects. Normalization of NPC function could be a novel therapeutic strategy for neurodegenerative disorders in which AMPA receptor-mediated excitotoxicity is a contributory factor.
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