Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis

Abstract

Responsible for the majority of excitatory activity in the central nervous system (CNS), glutamate interacts with a range of specific receptor and transporter systems to establish a functional synapse. Excessive stimulation of glutamate receptors causes excitotoxicity, a phenomenon implicated in both acute and chronic neurodegenerative diseases [e.g., ischemia, Huntington's disease, and amyotrophic lateral sclerosis (ALS)]. In physiology, excitotoxicity is prevented by rapid binding and clearance of synaptic released glutamate by high-affinity, Na þ -dependent glutamate transporters and amplified by defects to the glutamate transporter and receptor systems. ALS pathogenetic mechanisms are not completely understood and characterized, but excitotoxicity has been regarded as one firm mechanism implicated in the disease because of data obtained from ALS patients and animal and cellular models as well as inferred by the documented efficacy of riluzole, a generic antiglutamatergic drug, has in patients. In this article, we critically review the several lines of evidence supporting a role for glutamate-mediated excitotoxicity in the death of motor neurons occurring in ALS, putting a particular emphasis on the impairment of the glutamate-transport system. Antioxid. Redox Signal. 11, 1587-1602. Glutamate in the Central Nervous SystemL -Glutamate is the predominant excitatory neurotransmitter in the central nervous system (CNS). A nonessential amino acid, glutamate is continuously converted to a-ketoglutarate through deamination by glutamate dehydrogenase or by transamination by one of the transaminases and metabolized through the tricarboxylic acid cycle to succinate, fumarate, and malate, successively. Glutamate is also the product of the deamination of glutamine by phosphateactivated glutaminase, a mitochondrial and possibly neuronspecific enzyme (80). Synaptically released glutamate activates a family of ligand-gated ion channels (ionotropic receptors) and G protein-coupled receptors (metabotropic receptors), and its action is terminated by specific reuptake systems located mainly in astrocytes surrounding the synapse. In astrocytes, glutamate is then converted into glutamine, which does not have neurotransmitter properties and can be released and made available for neurons to convert it back to glutamate through a glutamine-reuptake system. Glutamate is then packed by vesicular glutamate transporters in synaptic vesicles, ready to be released again (35,129) (Fig. 1).

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“…A common assumption is that pathogenic mechanisms must converge because the different forms of ALS are clinically indistinguishable. Supporting this idea, glutamate excitotoxicity and mitochondria dysfunction are shared by fALS and sALS (25,28,29). In addition, mutations and proteinaceous inclusions of TDP-43 and FUS, and more recently of ubiquilin 2, have been identified in both fALS and sALS (30,31).…”

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“…As in other disorders, the damage of these neurons occurs by the combination of excitotoxicity, chronic inflammation, oxidative stress, protein aggregation, and other cytotoxic events [146][147][148]. The most abundant cases of ALS are sporadic [149], but the disease may be also familiar, associated with mutations in genes encoding for superoxide dismutase-1 (SOD-1), TAR-DNA binding protein-43 (TDP-43) or FUS (fused in sarcoma) protein, as well as the more recent CCGGGG hexanucleotide expansion in C9orf72 [145,148].…”

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“…One likely molecule that could be adversely affected by BMAA is the glutamate transporter, whose defective expression has been linked to ALS [81]. Glutamate excitotoxicity in motor neurons is associated with ALS, and this could be caused by an impaired glutamate transport system.…”