A Jacob/nsmf gene knockout does not protect against acute hypoxia- and NMDA-induced excitotoxic cell death

TY - JOUR

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 -