Sporadic Glutamate and Motor Neuron Disease.

Categorization and Sporadic Glutamate Cause of Motor Neurons Disease

This article will follow on from the previous motor neurone article on the familial causes, here the focus will be on the categorization and the glutamate sporadic origin of the disease.

How is MND categorised?

Diseases of the motor neurones are classified dependant on where the degeneration occurs; this is either the upper motor neurons, the lower motor neurons or both; or whether the disease is sporadic or familial (hereditary).

Upper motor neurons, also known as corticospinal neurons, originate in the motor region of the cerebral cortex (precentral gyrus) of the frontal lobe. These neurons project from here to the brain stem where they synapse with lower motor neurons to deliver nerve signals. Glutamate is released from corticospinal neurons. Lower motor neurons, also known as anterior horn cells are found in the in the anterior grey column (ventral horn) of the spinal cord, and cranial nuclei within the brain stem. These neurons give control of movement to arms, legs, face, chest, tongue and throat, and act as a link between upper motor neurons and muscle fibres.

Amyotrophic lateral sclerosis (ALS) affects both upper and lower motor neurons, Primary lateral Sclerosis affects just upper motor neurons, Muscular atrophy affects just the lower, and Progressive Bulbar Palsy affects the lowest motor neurons of the brain stem.

Sporadic Glutamate

Glutamate is the most abundant excitatory neurotransmitter. A neurotransmitter is a type of messenger that transports information from one nerve to the next. When glutamate is synaptically released from the neuron it binds to ionotropic and metabotropic receptors causing depolarisation (activation) of the adjacent cell. The activity of glutamate is terminated by specific glutamate reuptake transporters located on surrounding astrocytes and neurons, these glutamate up-takers are known as EAAT 1-5 (excitatory amino acid transporter).

Figure 1: Shows the synthesis and lysis pathway of glutamate.

(Singuer Associates, Inc. 2001)

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There is evidence to suggest some people with MND have become more sensitive to glutamate (Foran, E. 2009). Glutamate is a powerful excitatory neurotransmitter therefore abnormally high concentrations can cause over excitation of a neuron, known as excitotoxicity. Excitotoxicity can also be caused by dysregulated activity of glutamate receptors; they may themselves become overly sensitive to glutamate meaning they are activated by a lower than normal concentration. Prolongation of excitotoxicity leads to the death of the neurons. Alternatively ineffective or dysfunctional glutamate re-uptake transporters leads to a build-up of glutamate around the synapse; again causing over excitation and cell death. The reduced number of neurons due to degeneration means signals from the motor cortex can no longer effectively travel to muscles causing the symptoms of motor neurone disease.

One receptor found to be particularly important is the EEAT2 (Tanaka, et al. 1997). It was demonstrated by Rothstein and team (1996) that the removal of this receptor in knockout mice produced an increased extracellular level of glutamate along with increased progressive paralysis and neurodegeneration in rats; suggesting that the EEAT2 glutamate re-uptake transporter is essential for maintaining normal levels of glutamate.

Riluzole Treatment

Riluzole is the only FDA-approved drug based treatment for amyotrophic lateral sclerosis (ALS) form of MND which can prolong survival by an average of 3 months found in two large clinical trials performed by Bensimon and Lacomblez (1996). Riluzole is an antiglutamatergic drug which regulates the release of glutamate and postsynaptic receptor activation and inhibits voltage-sensitive channels from opening (Andreadou, E. 2008). Plasma levels of glutamate and other excitatory neurotransmitters are reduced with this treatment as well as extracellular glutamate levels decreased by the upregulation of the EEAT up-takers (Fumagalli, E. 2008).

Other sporadic causes

There are other sporadic causes of MND such as within the mitochondria, aggregates and RNA processing, and cell transport disruption. A new gene has now also been associated with MND called the NEK1 due to money raised by the Ice Bucket Challenge started in 2014. The same challenge lead to 6 new research projects being funded for research into ALS which will be my next NeuroBlog post!

Author: Laura Ellis

Editor: Molly Campbell

References

Andreadou, E., Kapaki, E., Kokotis, P., Paraskevas, G., Katsaros, N., Libitaki, G., Zis, V., Sfagos, C. and Vassilopoulos, D. (2008). Plasma glutamate and glycine levels in patients with amyotrophic lateral sclerosis: The effect of riluzole treatment. Clinical Neurology and Neurosurgery, 110(3), pp.222-226.

Foran, E. and Trotti, D. (2009). Glutamate Transporters and the Excitotoxic Path to Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis. Antioxidants & Redox Signaling, 11(7), pp.1587-1602.

Fumagalli, E., Funicello, M., Rauen, T., Gobbi, M. and Mennini, T. (2008). Riluzole enhances the activity of glutamate transporters GLAST, GLT1 and EAAC1. European Journal of Pharmacology, 578(2-3), pp.171-176.

Lacomblez, L., Bensimon, G., Meininger, V., Leigh, P. and Guillet, P. (1996). Dose-ranging study of riluzole in amyotrophic lateral sclerosis. The Lancet, 347(9013), pp.1425-1431.

Rothstein, J., Dykes-Hoberg, M., Pardo, C., Bristol, L., Jin, L., Kuncl, R., Kanai, Y., Hediger, M., Wang, Y., Schielke, J. and Welty, D. (1996). Knockout of Glutamate Transporters Reveals a Major Role for Astroglial Transport in Excitotoxicity and Clearance of Glutamate. Neuron, 16(3), pp.675-686.

Tanaka, K. (1997). Epilepsy and Exacerbation of Brain Injury in Mice Lacking the Glutamate Transporter GLT-1. Science, 276(5319), pp.1699-1702.

 

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