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Ras-like Gem GTPase induced by Npas4 promotes activity-dependent neuronal tolerance for ischemic stroke
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2021
- Publisher :
- Proceedings of the National Academy of Sciences, 2021.
-
Abstract
- Significance Stroke is the second leading cause of death and the most frequent cause of disability in adults. After stroke, most ischemic neurons die and a few neurons live, leading to brain dysfunction; yet, genes involved in both neuronal survival and death remain poorly understood. Here, we found that the activity-dependent transcription factor Npas4 is essential for acquisition of neuronal tolerance to ischemia. Moreover, a systematic search for Npas4-downstream genes identified Gem, which encodes Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of voltage-gated Ca2+ channels to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death. Our findings suggest that Gem expression via Npas4 promotes neuroprotection and neuroplasticity in injured and healthy brains, respectively.<br />Ischemic stroke, which results in loss of neurological function, initiates a complex cascade of pathological events in the brain, largely driven by excitotoxic Ca2+ influx in neurons. This leads to cortical spreading depolarization, which induces expression of genes involved in both neuronal death and survival; yet, the functions of these genes remain poorly understood. Here, we profiled gene expression changes that are common to ischemia (modeled by middle cerebral artery occlusion [MCAO]) and to experience-dependent activation (modeled by exposure to an enriched environment [EE]), which also induces Ca2+ transients that trigger transcriptional programs. We found that the activity-dependent transcription factor Npas4 was up-regulated under MCAO and EE conditions and that transient activation of cortical neurons in the healthy brain by the EE decreased cell death after stroke. Furthermore, both MCAO in vivo and oxygen-glucose deprivation in vitro revealed that Npas4 is necessary and sufficient for neuroprotection. We also found that this protection involves the inhibition of L-type voltage-gated Ca2+ channels (VGCCs). Next, our systematic search for Npas4-downstream genes identified Gem, which encodes a Ras-related small GTPase that mediates neuroprotective effects of Npas4. Gem suppresses the membrane localization of L-type VGCCs to inhibit excess Ca2+ influx, thereby protecting neurons from excitotoxic death after in vitro and in vivo ischemia. Collectively, our findings indicate that Gem expression via Npas4 is necessary and sufficient to promote neuroprotection in the injured brain. Importantly, Gem is also induced in human cerebral organoids cultured under an ischemic condition, revealing Gem as a new target for drug discovery.
- Subjects :
- Male
Programmed cell death
Calcium Channels, L-Type
neuroplasticity
Ischemia
neural activity–dependent
Neuroprotection
In vivo
Basic Helix-Loop-Helix Transcription Factors
ischemic stroke
medicine
Animals
Humans
Small GTPase
Npas4
Transcription factor
Monomeric GTP-Binding Proteins
Mice, Knockout
Neurons
Environmental enrichment
Multidisciplinary
Cell Death
Chemistry
Infarction, Middle Cerebral Artery
Depolarization
Biological Sciences
medicine.disease
Cell biology
Mice, Inbred C57BL
Organoids
HEK293 Cells
Calcium
neuroprotection
Neuroscience
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....1d16a02821a638f2d7fb70ec42d1f617