Amyotrophic Lateral Sclerosis Part 11

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Amyotrophic Lateral Sclerosis Part 11382 Amyotrophic Lateral SclerosisFig. 1. Mutant SOD1 in astrocytes affecting (motor) neuron survival.3. Astrocytes in excitotoxicityIn addition to the clear inflammatory role that astrocytes play in ALS, they also contribute tothe mechanism of excitotoxicity. Their effect in the latter mechanism is two-fold: firstly,astrocytes facilitate the removal of excessive glutamate at the synaptic cleft and secondly,they affect the calcium permeability of AMPA receptors of motor neurons.3.1 Excitotoxicity in ALS explainedGlutamate is the initiator of excitotoxicity in ALS. This neurotransmitter is the mostabundant excitatory neurotransmitter in the brain and binds to NMDA, AMPA, and kainate(ionotropic) and metabotropic glutamate receptors (mGluR). Packaged into vesicles by thepre-synaptic neuron, glutamate is released into the synaptic cleft by the fusion of vesicles tothe membrane of the neuron to excite the post synaptic neuron. This process is inhibited byriluzole (Siniscalhi et al., 1999). Increased levels of glutamate are detected in fALS, sALS(Fiszman et al., 2010; Spreux-Varoquaux et al., 2002) and is confirmed in spinal cords of ALSmice and rats. The detrimental role of glumate in the disease is demonstrated by thepronounced cell death that occurs to neurons in vitro when exposed to low levels ofglutamate, even as low as physiologically detected in CSF (Cid et al., 2003). To furtherillustrate the detrimental role of glutamate in ALS, administration of compounds that blockthe formation of glutamate increase cell survival, both in vivo and in vitro (Cid et al., 2003).3.2 Astrocytes in excitotoxicity in ALS: EAAT2/GLT-1After glutamate release from the pre-synaptic neuron and binding of glutamate toionotropic or metabotropic receptors on the post-synapse (increasing the concentration of 383The Astrocytic Contribution in ALS: Inflammation and Excitotoxicityintracellular calcium), glutamate is recycled for further use by the glial and endothelial cells,including astrocytes. Astrocytic glutamate re-uptake occurs by the glutamate transportersexcitatory amino acid transporter 1 (EAAT1) and excitatory amino acid transporter 2(EAAT2; also known as glutamate aspartate transporter (GLAST1) and glutamatetransporter 1 (GLT-1), respectively). These transporters internalise glutamate, eg. into theastrocyte, for conversion to glutamine that is returned to the pre-synaptic neuron to berelease again as glutamate (Laake et al., 1995).Decreased glutamate uptake and EAAT2 protein levels are a common feature in both fALSand sALS and both in vitro and in vivo model systems (Staats and Van Den Bosch, 2009). Invitro transfection of primary cultured astrocytes with either mutant SOD1 or wild typehuman SOD1 down-regulates EAAT2 post transcriptionally (Tortarolo et al., 2004) anddecreases EAAT2 transcription (Yang et al., 2009). Accordingly, glutamate transport isdecreased in a neuronal cell line by mutant SOD1 transfection (Sala et al., 2005).Interestingly, this down-regulation also occurs in ALS model rats at pre-symptomatic stagesthrough to end stage (Howland et al., 2002), at end stage only (Warita et al., 2002), in ALSmodel mice at end stage (Bendotti et al., 2001; Guo et al., 2010) and in post mortem patientspinal cords (Sasaki et al., 2001). In addition, in patient material the loss of EAAT2 anddecreased tissue glutamate transport does not coincide with decreased levels of geneexpression (Bristol and Rothstein, 1996), indicating that the loss is induced posttranscriptionally, also in humans. Interestingly, a decrease of EAAT2 protein levels is notonly in mutant SOD1 ALS models, but also a model of ALS/PDC (Wilson et al., 2003). Inthis model wild-type mice are fed with washed cycad flour containing β-methylamino-alanine (BMAA), which causes an ALS-like phenotype (Wilson et al., 2002). Although theloss of EAAT2 in ALS is apparent, it remains unclear whether this post transcriptional lossof EAAT2 proceeds or follows the loss of motor neurons.3.3 Targeting (astrocytic) EAAT2To assess whether the loss of glutamate transport or the loss of EAAT2 specifically results inmotor neuron loss, pharmacological and genetic tools have been used. To begin, researchconducted by pharmacologically inhibiting glutamate transport in the rat spinal cord, failedto show any motor neuron loss despite the increased levels of glutamate (Tovar et al., 2009).In contrast, a similar experiment has been performed to address whether EAAT2 lossspecifically induces motor neuron loss. EAAT2 null mice live for approximately 6 weeksbefore they succumb to epileptic seizures and are vulnerability to acute brain injury (Tanakaet al., 1997). To this end, heterozygous mice demons ...