P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease
Highlights
► NMDAR-mediated pro-death pathways investigated in YAC128 Huntington disease mouse. ► Increased extrasynaptic PSD-95 and its interaction with GluN2B in YAC128 striatum. ► Cell death-associated proteins p38- and JNK-MAPK are activated in YAC128 striatum. ► NMDAR/PSD-95 complex required for NMDA-stimulated YAC128 striatal p38 activation. ► P38 inhibition or disruption of NMDAR/PSD-95 complex reduces YAC128 striatal death.
Introduction
Evidence suggests N-methyl-d-aspartate (NMDA)-type glutamate receptors (NMDARs) play a critical role in several neurodegenerative diseases, including Huntington disease (HD) (Cowan and Raymond, 2006, Waxman and Lynch, 2005). HD is caused by a polyglutamine (polyQ) expansion > 35 in the protein huntingtin (htt; The Huntington's Disease Collaborative Research Group, 1993). Striatal GABAergic medium-sized spiny neurons (MSNs), which are enriched in GluN2B subunit-containing NMDARs (Christie et al., 2000, Landwehrmeyer et al., 1995, Li et al., 2003), are most severely affected in HD (Vonsattel and DiFiglia, 1998). Previous work suggests GluN2B-containing NMDARs are functionally altered and contribute to neuronal dysfunction and susceptibility to apoptosis in mouse and cellular models of HD (Chen et al., 1999, Fan et al., 2007, Heng et al., 2009, Li et al., 2004, Milnerwood et al., 2010, Song et al., 2003, Tang et al., 2005, Zeron et al., 2001, Zeron et al., 2002, Zhang et al., 2008).
In cultured cortical and hippocampal neurons, evidence indicates that synaptic NMDAR activation triggers cell survival pathways, and stimulation of the whole-cell population of NMDARs and/or selective activation of extrasynaptic NMDARs (Ex-NMDARs) signals cell death (Leveille et al., 2008, Soriano and Hardingham, 2007, Vanhoutte and Bading, 2003). Some studies suggest GluN2B-containing receptors predominate at extrasynaptic sites whereas GluN2A-containing receptors are preferentially targeted to the postsynaptic density (PSD) (Barria and Malinow, 2002, Rumbaugh and Vicini, 1999, Tovar and Westbrook, 1999), and that NMDAR complexes containing GluN2B facilitate cell death signaling while GluN2A-containing NMDARs promote neuronal survival (Chen et al., 2007, Liu et al., 2007, Tu et al., 2010). Recently, we showed that GluN2B expression was significantly increased in striatal extrasynaptic (non-PSD) membrane fractions in presymptomatic yeast artificial chromosome mice expressing htt with 128 polyQ (YAC128 mice) compared to YAC18 mice; the shift in GluN2B-containing receptor localization was associated with increased Ex-NMDAR current and reduced nuclear CREB activation in YAC128 striatum (Milnerwood et al., 2010).
PSD-95 may contribute to NMDAR-mediated excitotoxicity by stabilizing surface receptors and anchoring signaling proteins such as nNOS near NMDAR-mediated calcium influx (Roche et al., 2001, Sattler and Tymianski, 2000, Sattler et al., 1999). The NMDAR/PSD-95/nNOS pathway is critical for excitotoxic cell death in a rodent stroke model (Aarts et al., 2002), and this pathway is down-regulated with development of resistance to NMDAR toxicity in the N171-82Q transgenic mouse model of HD (Jarabek et al., 2004). Notably, GluN2B binding with PSD-95 is increased in striatal tissue from young, excitotoxin-sensitive YAC mice with increasing htt polyQ length and contributes to elevated NMDA toxicity in cultured MSNs, independently of nNOS (Fan et al., 2009). However, the mechanism by which mutant htt (mhtt)-enhanced NMDAR/PSD-95 binding contributes to increased striatal NMDA toxicity in HD is not known.
Mitogen-activated protein kinases (MAPKs) form a superfamily of serine/threonine protein kinases that are highly responsive to diverse extracellular signals in adult mammalian neurons, including activation of NMDARs (Haddad, 2005, Wang et al., 2004, Wang et al., 2007). In particular, the extracellular signal-regulated protein kinase (ERK), p38, and c-Jun amino-terminal kinase (JNK) MAPKs are differentially activated by glutamate receptor subtypes, play distinct roles in regulating synaptic plasticity, gene expression, and neuronal survival, and have emerged as targets for neurodegenerative diseases (Haddad, 2005, Harper and Wilkie, 2003, Wang et al., 2004).
Activation of Ex-NMDARs triggers nuclear translocation of the death-program transcription factor FoxO3a, which can be reduced by either p38 or JNK inhibitors in hippocampal neurons (Dick and Bading, 2010). Consistent with this finding, recent data show that two distinct excitotoxic pathways contribute to NMDA-induced cell death in cortical neurons: one via p38 MAPK, which relies on NMDAR/PSD-95 binding and can be disrupted by Tat-NR2B9c without impacting pro-survival signaling; and the other via JNK, which is PSD-95-independent and also plays a role in non-neuronal cell death (Soriano et al., 2008). To investigate the mechanism of Tat-NR2B9c protection in YAC HD mice, we determined whether p38 MAPK and/or JNK pathways are altered by mhtt expression and contribute to enhanced excitotoxicity in MSNs of YAC HD mice.
Section snippets
Transgenic mice
All mice were housed and cared for, and tissue was harvested, according to guidelines of the University of British Columbia and the Canadian Council for Animal Care (under protocol A06-1534). The following lines of YAC transgenic mice — YAC18 (line 212) (Leavitt et al., 2001), YAC72 (line 2511) (Hodgson et al., 1999) and YAC128 (line55) (Graham et al., 2006) were used as models expressing full-length human htt containing 18 (control), 72, and 128 (pathogenic) polyQ repeats (18Q, 72Q, 128Q),
Increased PSD-95 localization and GluN2B/PSD-95 interactions in the striatal non-PSD compartment from pre-symptomatic YAC128 mice
Previously, we have shown that the HD phenotype in YAC128 mice is associated with increased localization, function and signaling of striatal extrasynaptic GluN2B-containing NMDARs (Milnerwood et al., 2010), which have been implicated in activation of cell death pathways (Hardingham and Bading, 2003, Papadia and Hardingham, 2007). Moreover, in striatal tissue from YAC128 mice, GluN2B and PSD-95 show increased co-association (Fan et al., 2009), an interaction known to contribute to NMDAR-mediated
Discussion
The NMDAR/PSD-95 interaction was shown previously to be a key contributor to excitotoxicity in cultured striatal neurons of a murine HD model (Fan et al., 2009), as well as in cultured WT rat cortical or hippocampal neurons, and to ischemic damage in a rodent stroke model (Aarts et al., 2002, Sattler and Tymianski, 2000, Sattler et al., 1999, Soriano et al., 2008). However, the cellular mechanisms underlying neuroprotection by disruption of the NMDAR/PSD-95 complex in the YAC HD mouse model
Conclusion
Together with previous studies, our findings demonstrate key roles for p38 and JNK MAPKs in NMDAR-mediated apoptosis in striatal neurons. Moreover, our results indicate an important contribution of NMDAR/PSD-95/p38 MAPK signaling in HD pathogenesis. The targeting of the NMDAR/PSD-95 interaction or p38 MAPK signaling may be beneficial to the development of biomarkers and treatments for HD.
Acknowledgments
We thank K. She and A.M. Craig for the YFP plasmid. The research was funded by operating grants to L.A.R. from the Canadian Institutes of Health Research (CIHR MOP-12699) and the Cure Huntington Disease Initiative (CHDI). C.M.G. is supported by a joint CIHR-Huntington Society of Canada fellowship award and is also a Hereditary Disease Foundation (HDF) Scholar.
References (93)
- et al.
Subunit-specific NMDA receptor trafficking to synapses
Neuron
(2002) - et al.
Deranged neuronal calcium signaling and Huntington disease
Biochem. Biophys. Res. Commun.
(2004) Synaptic plasticity: one STEP at a time
Trends Neurosci.
(2006)- et al.
Selective neuronal degeneration in Huntington's disease
Curr. Top. Dev. Biol.
(2006) - et al.
Synaptic activity and nuclear calcium signaling protect hippocampal neurons from death signal-associated nuclear translocation of FoxO3a induced by extrasynaptic N-methyl-d-aspartate receptors
J. Biol. Chem.
(2010) Inhibition of calpain cleavage of huntingtin reduces toxicity: accumulation of calpain/caspase fragments in the nucleus
J. Biol. Chem.
(2004)Adenosine and glutamate extracellular concentrations and mitogen-activated protein kinases in the striatum of Huntington transgenic mice. Selective antagonism of adenosine A2A receptors reduces transmitter outflow
Neurobiol. Dis.
(2004)Levels of mutant huntingtin influence the phenotypic severity of Huntington disease in YAC128 mouse models
Neurobiol. Dis.
(2006)N-methyl-d-aspartate (NMDA) and the regulation of mitogen-activated protein kinase (MAPK) signaling pathways: a revolving neurochemical axis for therapeutic intervention?
Prog. Neurobiol.
(2005)- et al.
The Yin and Yang of NMDA receptor signalling
Trends Neurosci.
(2003)
A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration
Neuron
The effect of aging on p38 signaling pathway activity in the mouse liver and in response to ROS generated by 3-nitropropionic acid
Mech. Ageing Dev.
Age-associated changes in SAPK/JNK and p38 MAPK signaling in response to the generation of ROS by 3-nitropropionic acid
Mech. Ageing Dev.
Activation and involvement of p38 mitogen-activated protein kinase in glutamate-induced apoptosis in rat cerebellar granule cells
J. Biol. Chem.
SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family
Neuron
Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo
Am. J. Hum. Genet.
Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease
Neurobiol. Aging
Activation of MLK2-mediated signaling cascades by polyglutamine-expanded huntingtin
J. Biol. Chem.
Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice
Neuron
Immunocytochemical localization of the striatal enriched protein tyrosine phosphatase in the rat striatum: a light and electron microscopic study with a complementary DNA-generated polyclonal antibody
Neuroscience
The striatal-enriched protein tyrosine phosphatase gates long-term potentiation and fear memory in the lateral amygdala
Biol. Psychiatry
Tyrosine phosphatase STEP is a tonic brake on induction of long-term potentiation
Neuron
Implication of the JNK pathway in a rat model of Huntington's disease
Exp. Neurol.
Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-d-aspartate receptors
J. Biol. Chem.
DAPK1 interaction with NMDA receptor NR2B subunits mediates brain damage in stroke
Cell
Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation
Curr. Opin. Neurobiol.
Regulation of mitogen-activated protein kinases by glutamate receptors
J. Neurochem.
Mutant huntingtin enhances excitotoxic cell death
Mol. Cell. Neurosci.
Increased sensitivity to N-methyl-d-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease
Neuron
Potentiation of NMDA receptor-mediated excitotoxicity linked with intrinsic apoptotic pathway in YAC transgenic mouse model of Huntington's disease
Mol. Cell. Neurosci.
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.
Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions
Science
Molecular pathways to neurodegeneration
Nat. Med.
Cellular and molecular characterization of a brain-enriched protein tyrosine phosphatase
J. Neurosci.
Regulation of NMDA receptor trafficking and function by striatal-enriched tyrosine phosphatase (STEP)
Eur. J. Neurosci.
The PSD95-nNOS interface: a target for inhibition of excitotoxic p38 stress-activated protein kinase activation and cell death
J. Cell Biol.
Mutant huntingtin goes straight to the heart
Nat. Neurosci.
Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin
J. Neurochem.
Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent brain-derived neurotrophic factor gene regulation and limbic epileptogenesis
J. Neurosci.
Native N-methyl-d-aspartate receptors containing NR2A and NR2B subunits have pharmacologically distinct competitive antagonist binding sites
J. Pharmacol. Exp. Ther.
c-Jun N-terminal protein kinase (JNK) 2/3 is specifically activated by stress, mediating c-Jun activation, in the presence of constitutive JNK1 activity in cerebellar neurons
J. Neurosci.
Polyglutamine-modulated striatal calpain activity in YAC transgenic Huntington disease mouse model: impact on NMDA receptor function and toxicity
J. Neurosci.
A broad view of glutamate spillover
Nat. Neurosci.
Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease
J. Neurosci.
Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington's disease
J. Neurosci.
N-methyl-d-aspartate receptor subunit- and neuronal-type dependence of excitotoxic signaling through post-synaptic density 95
J. Neurochem.
Cited by (67)
4-Trifluoromethyl-(E)-cinnamoyl]-L-4-F-phenylalanine acid exerts its effects on the prevention, post-therapeutic and prolongation of the thrombolytic window in ischemia-reperfusion rats through multiple mechanisms of action
2022, Pharmacological ResearchCitation Excerpt :These results indicate that AE-18 was likely to be a potential NR2B antagonist. P38 and JNK1/2, members of the MAPK family, are up-regulated following NMDA stimulation [41]. A three-tiered kinase cascade is involved in regulating the activation of p38 and JNK1/2.
Inhibition of c-JNK/p38MAPK signaling pathway by Apigenin prevents neurobehavioral and neurochemical defects in ethidium bromide-induced experimental model of multiple sclerosis in rats: Evidence from CSF, blood plasma and brain samples
2021, Phytomedicine PlusCitation Excerpt :It has recently been proven that it occurs in neurodegenerative disorders such as ALS (Schellino et al., R 2019), Alzheimer's disease(AD) (Zhang et al., 2008; Li et al., 2011), Huntington's disease (HD) (J Fan et al., 2012; Perrin et al., V 2009), multiple sclerosis (MS) (Mestre et al., L 2009), neuropathic pain (Svensson et al., 2003). The p38MAPK-tau activation axis regulates neuroinflammation, acting remodeling, and tau hyperphosphorylation, all of which are thought to be involved in normal aging and neurodegenerative diseases such as multiple sclerosis (MS), Alzheimer's disease (AD) (Origliaet al., 2008), Parkinson's disease (PD) (Chen et al., 2018), Huntington's disease (HD) (Fan et al., J 2012), neurological dysfunctions (S Mehan et al., 2011). According to a previous study, oxidative stress aggravates EAE by activating the p38MAPK pathway, especially when antioxidant therapy significantly suppresses the p38MAPK pathway (Wang et al., 2017; Krementsov et al. DN 2014).
Modified Glutamatergic Postsynapse in Neurodegenerative Disorders
2021, NeuroscienceAnimal and model systems for studying cystic fibrosis
2018, Journal of Cystic FibrosisExcitotoxicity
2018, Comprehensive Toxicology: Third Edition