Glutamate pathway implication in amyotrophic lateral sclerosis: what is the signal in the noise?

Abstract

Abstract:The cause of the fatal motor neuron disease, amyotrophic lateral sclerosis (ALS), remains largely unknown. Most cases of ALS are sporadic and, for ∼20% of familial ALS patients, mutations in the superoxide dismutase-1 (SOD1) gene have been identified. Transgenic rodents overexpressing mutant SOD1 emulate the disease and constitute the best ALS animal model so far. Several lines of evidence suggest that ALS is a multifactorial condition. In this review, we discuss the question of the involvement of the glutamate pathways in ALS-induced motor neuron death. As such, we review the data implicating glutamate metabolism alterations, glutamatergic environmental toxins, glutamate transporter/receptor defects, and Ca 2+ -mediated glutamate toxicity in the etiopathogenesis of ALS. Given the published data, we contend that glutamate-induced neurotoxicity more likely precipitates motor neuron degeneration rather than being the initiating factor of ALS. Furthermore, we propose that glutamate-induced neurotoxicity participates in the ALS deadly molecular cascade only as an executioner to put an end to a series of molecular perturbations that have irreversibly compromised motor neuron function. This could provide an explanation for the modest effect of therapeutic strategies targeting the glutamatergic system, including the only currently FDA-approved ALS treatment, riluzole. As in diseased motor neurons, overwhelming Ca 2+ overload may be the converging point for glutamate, endoplasmic reticulum stress, and mitochondrial dysfunctional pathways, and only therapies targeting these simultaneously or targeting the earliest alterations initiating this deleterious cascade may have a real impact on halting ALS progression.

Microglia centered pathogenesis in ALS: insights in cell interconnectivity

“…In fact, although linkage between glutamate and neuroinflammation was suggested to have a role in potentiating MN death in a model mimicking ALS disease (Tolosa et al, 2011), other Authors have demonstrated that glutamate by itself was not able to induce MN damage in ALS (Tovar et al, 2009b). Indeed, it has been questioned the involvement of glutamate in ALS-induced MN death (Le Verche et al, 2011) and the cytotoxicity of the cerebrospinal fluid (CSF) from patients with ALS evidenced to not be related to glutamate (Gomez-Pinedo et al, 2013). …”

Glutamate transporters in health and disease

“…A study found that overexpression of GLT-1 in the cervical spinal cord of SOD1G93A mice with ALS did not protect motor neurons, preserve diaphragm function, or prolong animal survival, thus challenging the notion that EAAT2 is a primary factor in motor neuron degeneration in ALS [249]. It is thought that simultaneous targeting of calcium overload, endoplasmic reticulum stress, and mitochondrial dysfunction pathways may be necessary to halt ALS progression [250].…”