Role of excitotoxicity in the degeneration of motor neurones in ALS

Tortarolo, Massimo (2005). Role of excitotoxicity in the degeneration of motor neurones in ALS. PhD thesis The Open University.



Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder involving selective degeneration of motor neurones. In a proportion of patients, ALS is caused by mutations in copper/zinc superoxide dismutase (SOD1), and mice expressing these mutants develop a syndrome that resembles human ALS. Using SOD1G93A transgenic mice, the role of glutamate-mediated toxicity and related intracellular pathways in motor neurone death has been investigated. GluR2 AMPA receptor subunits were decreased in spinal motor neurones of SOD1G93A mice before symptom onset. Since GluR2-lacking receptors are highly permeable to Ca2+, a known trigger of excitotoxic neuronal death, this phenomenon may have a pathogenic role. In support of this, treatment with an AMPA antagonist, ZK-187638, ameliorated motor symptoms and prolonged the survival of SOD1G93A mice. GluR2-lacking receptors are also permeable to zinc, which can be highly toxic. In situ hybridisation showed low expression of the zinc extruder ZnT-1 on motor neurones, which may contribute to their vulnerability to excitotoxicity. Expression of glutamate transporters on astrocytes may also contribute to excitotoxic motor neurone death. In transgenic mice and in astrocytes transfected with SOD1G93A, immunocytochemistry. Western blotting, in situ hybridisation and RT-PCR revealed down-regulation of GLT-1 protein, but not mRNA in astrocytes. However, the time-course in mice suggests that GLT-1 downregulation is not a primary pathological event. Activation of p38MAPK, a kinase putatively involved in glutamate mediated neurotoxicity, was observed in motor neurones at the onset of the disease, but SB 239063, a p38MAPK inhibitor, did not ameliorate motor dysfunction or survival of SOD1G93A mice.
Altogether the results suggest that AMPA receptor mediated excitotoxicity is a primary cause of motor neurone degeneration in ALS. These observations may contribute to the development of new therapeutic strategies for this devastating disease.

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