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Modeling Age-Associated Neurodegenerative Diseases in Caenorhabditis elegans
Published on: August 15, 2020
carboxypeptidase E-ΔN, a neuroprotein transiently expressed during development protects embryonic neurons against
Xiao-Yan Qin1, Yong Cheng2, Saravana R K Murthy2
1Section on Cellular Neurobiology, Program on Developmental Neuroscience, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, United States of America; College of Life and Environmental Sciences, Minzu University of China, Beijing 100081, China.
Insights
A novel fetal protein, carboxypeptidase E-ΔN (CPE-ΔN), protects embryonic neurons from damage. It enhances FGF2 production, activating pathways that promote cell survival during critical neurodevelopmental periods.
Area of Science:
- Neuroscience
- Developmental Biology
- Molecular Biology
Background:
- Fetal neuroprotective proteins are crucial for embryonic development, particularly under stress conditions like maternal drug exposure.
- Glutamate excitotoxicity and oxidative stress can severely damage the developing fetal brain.
Purpose of the Study:
- To identify and characterize a novel neuroprotective protein, carboxypeptidase E-ΔN (CPE-ΔN), in embryonic neurons.
- To elucidate the molecular mechanisms underlying CPE-ΔN's neuroprotective effects.
Main Methods:
- Identified CPE-ΔN as a transient splice variant of carboxypeptidase E (CPE) expressed in early embryonic stages.
- Transduced CPE-ΔN into embryonic neurons and assessed protection against glutamate and H2O2-induced cell death.
- Analyzed CPE-ΔN's effect on FGF2 mRNA transcription, secretion, and downstream signaling pathways (AKT, ERK, BCL-2, caspase-3).
Main Results:
- CPE-ΔN expression is transient, peaking in embryonic mouse brains and decreasing postnatally.
- Transduced CPE-ΔN protected embryonic cortical and hippocampal neurons from excitotoxicity and oxidative stress.
- CPE-ΔN enhanced FGF2 transcription and secretion, which activated AKT and ERK pathways, leading to increased BCL-2 and inhibited caspase-3 activity, promoting cell survival.
Conclusions:
- CPE-ΔN is a key neuroprotective factor during early embryonic development.
- The neuroprotective mechanism involves FGF2-mediated activation of AKT/ERK signaling, ultimately inhibiting apoptosis and enhancing neuronal survival.
Abstract:
Neuroprotective proteins expressed in the fetus play a critical role during early embryonic neurodevelopment, especially during maternal exposure to alcohol and drugs that cause stress, glutamate neuroexcitotoxicity, and damage to the fetal brain, if prolonged. We have identified a novel protein, carboxypeptidase E-ΔN (CPE-ΔN), which is a splice variant of CPE that has neuroprotective effects on embryonic neurons. CPE-ΔN is transiently expressed in mouse embryos from embryonic day 5.5 to postnatal day 1. It is expressed in embryonic neurons, but not in 3 week or older mouse brains, suggesting a function primarily in utero. CPE-ΔN expression was up-regulated in embryonic hippocampal neurons in response to dexamethasone treatment. CPE-ΔN transduced into rat embryonic cortical and hippocampal neurons protected them from glutamate- and H2O2-induced cell death. When transduced into embryonic cortical neurons, CPE-ΔN was found in the nucleus and enhanced the transcription of FGF2 mRNA. Embryonic cortical neurons challenged with glutamate resulted in attenuated FGF2 levels and cell death, but CPE-ΔN transduced neurons treated in the same manner showed increased FGF2 expression and normal viability. This neuroprotective effect of CPE-ΔN was mediated by secreted FGF2. Through receptor signaling, FGF2 activated the AKT and ERK signaling pathways, which in turn increased BCL-2 expression. This led to inhibition of caspase-3 activity and cell survival.
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