Sub-cellular localization and regulatory mechanisms of AMPA receptors in motor neurons of a murine model of familial Amyotrophic Lateral Sclerosis

Veglianese, Peitro (2007). Sub-cellular localization and regulatory mechanisms of AMPA receptors in motor neurons of a murine model of familial Amyotrophic Lateral Sclerosis. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000fa38

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease leading to progressive muscle wasting and paralysis and premature death. The disease is predominantly sporadic (sALS) in nature with approximately 10% of case inherited (familial ALS). In the present study, I have examined the subcellular distribution and expression of the AMPA receptor subunits and the proteins involved in their trafficking between the cytosol and postsynaptic membrane (ABP, PICK1 and NSF) in a mouse model of familial ALS (SOD1G93A mice) at different stages of the disease.

The main finding was a decrease of GluR2 AMPA receptor subunit selectively in cytosol, but not in synaptic membrane of spinal motor neurons of SOD1G93A mice before symptoms onset. This suggests that an impairment in the usually well-organized trafficking of the GluR2 AMPA is likely the cause of the increased degradation of this receptor subunit. In support of this, increased level of the trafficking protein NSF, able to increase the delivery of GluR2 at the cell surface, was reported selectively in the motor neurons at the presymptomatic stage of the disease in SOD1G93A mice.

Since GluR2 plays an important role in regulating the calcium entrance in the cells by the AMPA receptors, I hypothesise that the increase of NSF may be an attempt to protect motor neurons from excitotoxicity by maintaining the sufficient levels of GluR2 subunit in the membrane. However, since an overall degradation of this subunit occurs in the motor neurons, this effect is probably no longer efficacious.

At symptomatic and end stage of the disease increased immunoreactivity of GluRl, 2 and 3 AMPA receptor subunits was found in the activated glial cells. Although there are evidences of a role of reactive glia in favouring the neuronal excitotoxicity, the relevance of this effect needs to be investigated.