The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency
Highlights
• Glutamate at physiological doses induces DNA damage. • This DNA damage is rapidly repaired. • AP endonuclease is induced in the process. • Glutamate dysregulation may lead to defects in DNA repair.
Section snippets
Glutamate signaling
Glutamate is one of twenty essential amino acids and is the main excitatory neurotransmitter in the mammalian central nervous system (CNS). Glutamate has been reported to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival (Mattson, 2008). The concentration of glutamate is strictly maintained in the CNS, and glutamate released into the synaptic gap is promptly recovered by neurons and/or glial cells (especially astrocytes) via the glutamate transporter 1 (Fig. 1).
Glutamate, oxidative stress and DNA base excision repair
Glutamate signaling induces mitochondrial Ca2+ uptake, and an increase in mitochondrial respiration can result in elevated levels of superoxide and other genotoxic free radicals (Fig. 2) (Sengpiel et al., 1998, Chinopoulos et al., 2000). The reactive oxygen species (ROS), together with rapid mitochondrial membrane permeability changes, trigger cell death in a process termed excitotoxicity (Reynolds, 1999, Mattson, 2003).
High concentrations of glutamate can cause neuronal death, which typically
Glutamate and neurodegeneration
Many studies have reported that glutamate excitotoxicity increases oxidative stress in both in vitro and in vivo models, and accumulating evidence indicates that glutamate-induced oxidative stress contributes to neuronal death in neurodegenerative diseases (Mattson, 2003). Aging and disease-specific processes, such as amyloid accumulation in Alzheimer's disease and cerebral ischemia in stroke, perturb glutamate homeostasis and increase sensitivity of neurons to glutamate which can produce
Conclusions
Emerging evidence suggest that physiological levels of activation of synaptic glutamate receptors can up-regulate DNA repair systems, thereby increasing the resiliency of the neurons and resulting in reduced vulnerability to age-related degeneration and acute injury. We have found that glutamate signaling can enhance BER by a mechanism involving Ca2+-mediated activation of CREB, which induces the expression of APE1 (Yang et al., 2010). The calcium – CREB pathway has previously been shown to
Acknowledgement
This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.
References (81)
- et al.
Deranged neuronal calcium signaling and Huntington disease
Biochem. Biophys. Res. Commun.
(2004) - et al.
CREB phosphorylation and dephosphorylation: a Ca(2+)- and stimulus duration-dependent switch for hippocampal gene expression
Cell
(1996) - et al.
Replicating Huntington's disease phenotype in experimental animals
Prog. Neurobiol.
(1999) - et al.
Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline
DNA Repair (Amst.)
(2003) - et al.
The many faces of CREB
Trends Neurosci.
(2005) Glutamate neurotoxicity and diseases of the nervous system
Neuron
(1988)Neurodegeneration in multiple sclerosis: the role of oxidative stress and excitotoxicity
J. Neurol. Sci.
(2008)- et al.
Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133
Cell
(1989) - et al.
Calcium-dependent mitochondrial superoxide modulates nuclear CREB phosphorylation in hippocampal neurons
Mol. Cell. Neurosci.
(2003) - et al.
ALS-linked Cu/Zn-SOD mutation increases vulnerability of motor neurons to excitotoxicity by a mechanism involving increased oxidative stress and perturbed calcium homeostasis
Exp. Neurol.
(1999)
Suppression of uracil-DNA glycosylase induces neuronal apoptosis
J. Biol. Chem.
Coordination of steps in single-nucleotide base excision repair mediated by apurinic/apyrimidinic endonuclease 1 and DNA polymerase beta
J. Biol. Chem.
Interactions between entorhinal axons and target hippocampal neurons: a role for glutamate in the development of hippocampal circuitry
Neuron
Impaired glutamate homeostasis and programmed cell death in a chronic MPTP mouse model of Parkinson's disease
Exp. Neurol.
Oxidative damage to mitochondrial DNA in Huntington's disease parietal cortex
Neurosci. Lett.
DNA-polymerase alpha, beta, delta and epsilon activities in isolated neuronal and astroglial cell fractions from developing and aging rat cerebral cortex
Int. J. Dev. Neurosci.
Linking DNA damage and neurodegeneration
Trends Neurosci.
Widespread distribution of DNA glycosylases removing oxidative DNA lesions in human and rodent brains
DNA Repair (Amst.)
Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite
Toxicol. Appl. Pharmacol.
The multifunctional DNA repair/redox enzyme Ape1/Ref-1 promotes survival of neurons after oxidative stress
DNA Repair (Amst.)
Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's disease
Neurobiol. Dis.
Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons
Am. J. Pathol.
Increased oxidative damage to DNA in an animal model of amyotrophic lateral sclerosis
Free Radic. Res.
Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra
J. Neurochem.
A new APE1/Ref-1-dependent pathway leading to reduction of NF-kappaB and AP-1, and activation of their DNA-binding activity
Nucleic Acids Res.
Multiple sequence elements of a single functional class are required for cyclic AMP responsiveness of the mouse c-fos promoter
Mol. Cell. Biol.
Increased oxidative damage to DNA in a transgenic mouse model of Huntington's disease
J. Neurochem.
The amyloid beta protein induces oxidative damage of mitochondrial DNA
J. Neuropathol. Exp. Neurol.
Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia
Ann. Neurol.
Induction of DNA polymerase beta-dependent base excision repair in response to oxidative stress in vivo
Carcinogenesis
Up-regulation of base excision repair correlates with enhanced protection against a DNA damaging agent in mouse cell lines
Nucleic Acids Res.
Exacerbated responses to oxidative stress by an Na(+) load in isolated nerve terminals: the role of ATP depletion and rise of [Ca(2+)](i)
J. Neurosci.
Postfusional regulation of cleft glutamate concentration during LTP at ‘silent synapses’
Nat. Neurosci.
Glutamate excitotoxicity and therapeutic targets for amyotrophic lateral sclerosis
Expert. Opin. Ther. Targets
A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide
J. Neurochem.
A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration
PLoS Genet.
The glutamate receptor ion channels
Pharmacol. Rev.
Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases
Acta Pharmacol. Sin.
Increased postischemic brain injury in mice deficient in uracil-DNA glycosylase
J. Clin. Invest.
Mutant huntingtin impairs Ku70-mediated DNA repair
J. Cell Biol.
Cited by (68)
The hormesis principle of neuroplasticity and neuroprotection
2024, Cell MetabolismImmunocytochemical localization of the AMPA glutamate receptor subtype GluR2/3 in the squid optic lobe
2022, Acta HistochemicaCitation Excerpt :Different types of neurons within the OL could send efferent visuomotor signals to or receive afferent inputs from various regions of the CNS through the optic tract (Chung et al., 2020; Jacobs, 2022; Williamson and Chrachri, 2004; Young, 1974). As a major excitatory neurotransmitter, glutamate is involved in various activities in the vertebrate CNS, such as brain plasticity (Sheng and Kim, 2002), learning and memory (Alkadhi, 2021; Bliss and Collingridge, 1993), development (Matsugami et al., 2006), and neuroprotection (Yang et al., 2011), and widely distributed in various areas of the central visual system (Kerschensteiner, 2016; Massey, 1990). Glutamate is also abundantly found in the cephalopod CNS (D’Aniello et al., 1995; Messenger, 1996; Palumbo et al., 1999), especially in the OL (D’Aniello et al., 2005; Piscopo et al., 2007), and plays a key role in learning and memory (Hochner et al., 2003; Shomrat et al., 2015), body patterning (Tublitz et al., 2006), and brain development (Lee et al., 2013).
PSA mimetic 5-nonyloxytryptamine protects cerebellar neurons against glutamate induced excitotoxicity: An in vitro perspective
2021, NeuroToxicologyCitation Excerpt :Glutamate is a major excitatory neurotransmitter accounting for 50 % of synaptic connections in the nervous system (Assiset al., 2014). Glutamate neurotransmission is implicated in many aspects of the brain functioning like cognition, neuronal survival, neuronal differentiation, learning and behavior etc. (Dingledine et al., 1999; Mattson, 2008; Yang et al., 2011). However, excessive glutamate concentration causes activation of Ca2+ sensitive proteases like ‘Calpain’ which in turn cause cytoskeletal protein degradation and subsequent axonal degeneration (Springer et al., 1997; O’Hanlon et al., 2003).
Exercise, redox system and neurodegenerative diseases
2020, Biochimica et Biophysica Acta - Molecular Basis of DiseaseEnabling biodegradable functional biomaterials for the management of neurological disorders
2019, Advanced Drug Delivery ReviewsCitation Excerpt :Excessive glutamate release can overstimulate the brain and cause excitotoxicity, triggering neuronal degeneration and cell death. The excitotoxicity has been implicated in many neurological diseases including Parkinson's disease, Alzheimer's disease, Huntington disease, seizures, stroke, epilepsy, and amyotrophic lateral sclerosis [176,177]. Dopamine is another vital neurotransmitter that regulates the reward and pleasure centers of the brain, controls the release of various hormones, and affects motor behaviors.
- 1
These authors contributed equally to this work.
- 2
These senior authors contributed equally to this work.