PMC:6610326 / 77316-84674
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/6610326","sourcedb":"PMC","sourceid":"6610326","source_url":"https://www.ncbi.nlm.nih.gov/pmc/6610326","text":"Excitotoxicity\nExcitotoxicity is the process by which neurons degenerate from excessive stimulation by neurotransmitters such as glutamate, due to overactivation of NMDA or AMPA receptors. This can result from pathologically high levels of glutamate, or from excitotoxins like NMDA and kainic acid, which allow high levels of Ca2+ to enter the cell. One line of evidence supporting a role for excitotoxicity in ALS is that riluzole, one of the only two drugs available for ALS patients, has anti-excitotoxic properties (Bensimon et al., 1994; Lacomblez et al., 1996). Riluzole inhibits the release of glutamate due to inactivation of voltage-dependant Na+ channels on glutamatergic nerve terminals (Doble, 1996). Previous studies have suggested that MNs that are less susceptible to excitotoxicity are less prone to degenerate (Hedlund et al., 2010; Brockington et al., 2013).\nCa2+ enters neurons through ligand-gated channels or voltage-gated channels such as the voltage-gated-L-type Ca2+ channel (Cav1.3), which mediates the generation of persistent inward currents (Xu and Lipscombe, 2001). Cav1.3 is differentially expressed in MN subtypes, with more in the spinal cord compared to the oculomotor and hypoglossal nuclei (Shoenfeld et al., 2014). This Ca2+ inward current increases early in disease course in MNs of SOD1G93A mice, which is associated with an increase in Cav1.3 expression.\nIn addition, the presence of atypical AMPA receptors in MNs compared to other neurons might render them more permeable to Ca2+. Functional AMPA receptors normally form a tetrameric structure composed, in various combinations, of the four subunits, GluR1, GluR2, GluR3, and GluR4. The Ca2+ conductance of these receptors differs markedly depending on whether GluR2 is a component of the receptor. However, in MNs, AMPA receptors express proportionately fewer GluR2 subunits relative to other types (Kawahara et al., 2003; Sun et al., 2005), which may render them more permeable to Ca2+ and thus more vulnerable to excitotoxic injury than other cells. Consistent with this notion, more GluR1 and GluR2 subunits are present in oculomotor neurons compared to spinal MNs in humans (Brockington et al., 2013), and treatment with AMPA/kainate of slice preparations from the rat lumbar spinal cord and midbrain results in more Ca2+ influx in spinal cord MNs compared to oculomotor neurons (Brockington et al., 2013). MNs in culture or in vivo are selectively vulnerable to glutamate receptor agonists, particularly those that stimulate AMPA receptors and induce excitotoxicity (Carriedo et al., 1996; Urushitani et al., 1998; Fryer et al., 1999; Van and Robberecht, 2000), whereas NMDA does not damage spinal cord MNs (Curtis and Malik, 1985; Pisharodi and Nauta, 1985; Hugon et al., 1989; Urca and Urca, 1990; Nakamura et al., 1994; Ikonomidou et al., 1996; Kruman et al., 1999). Moreover, ALS-vulnerable α-spinal cord MNs display greater AMPA receptor current density than other spinal neurons (Vandenberghe et al., 2000). Furthermore, when this density is reduced pharmacologically to levels similar to spinal neurons, these MNs are no longer vulnerable to activation of AMPA receptors. Similarly, when mutant SOD1G93A mice are crossed with mice overexpressing the GluR2 subunit in cholinergic neurons, the resulting progeny possess AMPA receptors with reduced permeability to Ca2+ and prolonged survival compared to SOD1G93A mice (Tateno et al., 2004), highlighting the importance of AMPA receptors and GluR2 in ALS.\nEditing of mRNA controls the ability of the GluA2 subunit to regulate Ca2+-permeability of AMPA receptors. RNA editing is a post-transcriptional modification (Gln; Q to Arg; R) in the GluA2 mRNA, and the AMPA receptor is Ca2+-impermeable if it contains the edited GluA2(R) subunit. Conversely, the receptor is Ca2+-permeable if it lacks GluA2 or if it contains the unedited GluA2(Q) subunit. Interestingly, spinal MNs in human ALS patients display less GluR2 Q/R site editing (Kawahara et al., 2004; Aizawa et al., 2010). GluR2 pre-mRNA is edited by the enzyme adenosine deaminase isoform 2 (ADAR2) (Kortenbruck et al., 2001) and reduced ADAR2 activity correlates with TDP-43 pathology in human MNs (Aizawa et al., 2010). Furthermore, when ADAR2 is conditionally knocked-down in MNs in mice, a decline in motor function and selective loss of MNs in the spinal cord and cranial motor nerve nuclei was observed (Hideyama et al., 2012). In contrast, MNs in the oculomotor nucleus were retained, despite a significant decrease in GluR2 Q/R site editing (Hideyama et al., 2010). Notably, cytoplasmic mislocalization of TDP-43 was present in the ADAR2-depleted MNs (Yamashita et al., 2012) and TDP-43 was also localized at the synapse, further highlighting a link between ADAR2, GluR2 and TDP-43 (Wang et al., 2008; Feiguin et al., 2009; Polymenidou et al., 2011; Gulino et al., 2015).\nMotor neurons may be vulnerable to excitotoxicity because they possess a lower capacity than other neurons to buffer Ca2+ upon stimulation (Van Den Bosch et al., 2006). Several electrophysiological studies have demonstrated that susceptible MNs in ALS have a limited capacity to buffer Ca2+ compared to resistant MNs (Lips and Keller, 1998, 1999; Palecek et al., 1999; Vanselow and Keller, 2000). Ca2+-binding proteins, such as calbindin D28K and parvalbumin, protect neurons from Ca2+-mediated cell death by enhancing Ca2+ removal after stimulation (Chard et al., 1993). In human autopsy specimens, both proteins are absent in MN populations lost early in ALS (cortical, spinal and lower cranial MNs), whereas MNs targeted later in disease course (Onuf’s nucleus, oculomotor, trochlear, and abducens MNs) expressed markedly more of each (Alexianu et al., 1994). Similarly, in pre-symptomatic SOD1G93A mice, lower levels of the Ca2+ binding ER chaperone calreticulin (CRT) were detected in vulnerable FF-MNs of the tibialis anterior muscle, compared to resistant MNs of the soleus (Bernard-Marissal et al., 2012). Knock-down of CRT in vitro was sufficient to trigger MN death by the Fas/NO pathway (Bernard-Marissal et al., 2012). Furthermore, reduced CRT levels and activation of Fas both trigger ER stress and cell death specifically in vulnerable SOD1G93A-expressing MNs (Bernard-Marissal et al., 2012). These studies suggest that expression of Ca2+-binding proteins may confer resistance to excitotoxic stimuli (Alexianu et al., 1994; Obál et al., 2006). However, overexpression of parvalbumin in high-copy SOD1G93A mice was beneficial (Laslo et al., 2000), although these findings have been challenged (Beers et al., 2001). Also, the loss or reduction of parvalbumin and calbindin D-28k immunoreactivity in large MNs at early stages in SOD1-transgenic mice suggest that these Ca2+-binding proteins contribute to the selective vulnerability of MNs (Sasaki et al., 2006). Conversely, parvalbumin levels are significantly less in oculomotor neurons from SOD1G93A mice compared to spinal cord MNs (Comley et al., 2015). Hence, these conflicting data argue against the involvement of Ca2+-binding proteins in oculomotor neuron resistance to degeneration. However, together these studies suggest that neuronal excitability and excitotoxicity are determinants of the selective vulnerability of spinal cord neurons, and the relative resistance of oculomotor neurons, in 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