A Jacob/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death
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A Jacob/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death. / Gomes, Guilherme M; Bär, Julia; Karpova, Anna; Kreutz, Michael R.
In: MOL BRAIN, Vol. 16, No. 1, 23, 11.02.2023.Research output: SCORING: Contribution to journal › Short publication › Research › peer-review
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T1 - A Jacob/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death
AU - Gomes, Guilherme M
AU - Bär, Julia
AU - Karpova, Anna
AU - Kreutz, Michael R
N1 - Micro report
PY - 2023/2/11
Y1 - 2023/2/11
N2 - Jacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-β and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimer's disease pathology and the absence of Jacob protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. nsmf is the gene that encodes for the Jacob protein. Here we show that organotypic hippocampal slices from wild-type and nsmf-/- mice display similar degrees of degeneration when exposed to either oxygen glucose deprivation or 50 µM NMDAto induce excitotoxicity. This lack of neuroprotection indicates that JaCS is mainly relevant in conditions of low level chronic extrasynaptic NMDAR activation that results in cellular degeneration induced by alterations in gene transcription.
AB - Jacob is a synapto-nuclear messenger protein that encodes and transduces the origin of synaptic and extrasynaptic NMDA receptor signals to the nucleus. The protein assembles a signalosome that differs in case of synaptic or extrasynaptic NMDAR activation. Following nuclear import Jacob docks these signalosomes to the transcription factor CREB. We have recently shown that amyloid-β and extrasynaptic NMDAR activation triggers the translocation of a Jacob signalosome that results in inactivation of the transcription factor CREB, a phenomenon termed Jacob-induced CREB shut-off (JaCS). JaCS contributes to early Alzheimer's disease pathology and the absence of Jacob protects against amyloid pathology. Given that extrasynaptic activity is also involved in acute excitotoxicity, like in stroke, we asked whether nsmf gene knockout will also protect against acute insults, like oxygen and glucose deprivation and excitotoxic NMDA stimulation. nsmf is the gene that encodes for the Jacob protein. Here we show that organotypic hippocampal slices from wild-type and nsmf-/- mice display similar degrees of degeneration when exposed to either oxygen glucose deprivation or 50 µM NMDAto induce excitotoxicity. This lack of neuroprotection indicates that JaCS is mainly relevant in conditions of low level chronic extrasynaptic NMDAR activation that results in cellular degeneration induced by alterations in gene transcription.
KW - Animals
KW - Mice
KW - Cell Death
KW - Gene Knockout Techniques
KW - Glucose
KW - Hypoxia/metabolism
KW - N-Methylaspartate/toxicity
KW - Neurons/metabolism
KW - Oxygen
KW - Receptors, N-Methyl-D-Aspartate/metabolism
KW - Synapses/metabolism
KW - Transcription Factors/metabolism
KW - Nerve Tissue Proteins/genetics
U2 - 10.1186/s13041-023-01012-2
DO - 10.1186/s13041-023-01012-2
M3 - Short publication
C2 - 36774487
VL - 16
JO - MOL BRAIN
JF - MOL BRAIN
SN - 1756-6606
IS - 1
M1 - 23
ER -