Ongoing research at Solomon Park Research Institute

In the search for an etiology of motor neuron disease (MND) also known as amyotrophic lateral sclerosis (ALS), three questions challenge any proposed cause. Why are motor neurons specifically affected? How does the degeneration in these cells spread from a primary site? Why is the condition irreversible?

Viral infections could account for the specificity of cells affected and the gradual spreading of pathology, however, no infectious agent has ever been found associated with MND despite Herculean efforts to isolate these particles or antibodies associated with them. Also, if the cause of MND were viral, it might be expected that some sufferers would recover, although it has not been proven that this does not occur and go undetected in some individuals. It also must be said that there still may be a viral particle or other agent, such as a prion, that is either unknown or is present in such small quantities or sequestered in such a way that it has not been detected in MND patients.

Autoimmunity could also explain the selective nature of the disease and since it is in the nervous system, the initiation site could be a breach in this system. Again, no evidence for autoimmunity has been successfully demonstrated in MND victims and in one study, whole body irradiation and bone marrow transplant did not affect the course of the disease.

Growth factors and other metabolic effects could also explain the degeneration of specific cells, such as motor neurons. The huge size of these cells compared to most other cells within and outside of the nervous system makes this a distinct possibility. Again, despite enormous efforts to explain MND by these factors, no correlation has withstood the test of time.

This leaves a genetic explanation for the specificity and tenacity of the disease. The major problem with this explanation is that MND is selective to certain cells while a genetic variant would be expected to be present in all the cells of the individual. One could postulate a somatic mutation early in development that affected only the nervous system, or even only the motor neurons, however, this does not explain the spreading of the condition. Such patterned age related effects are not unknown, however, and anyone that has experienced hair loss or graying knows that these age related conditions occur over time with very distinct patterns. Arguing against this is the fact that only ten per cent of MND is hereditary in nature and if there is a genetic basis for the disease, a higher heritability should be observed. In a large study examining twins in England, hereditability was estimated to be between 0.38 and 0.85 making this possibility quite viable. Finally, there is no reason to assume that the genetic basis of MND, or any disease for that matter, is only the result of a single gene or gene product, making it possible that certain traits could be inherited and only activated by other inherited traits or environmental factors.

At the present time, the major emphasis in research into MND is concentrated in elucidating genetic factors associated with the disease. This has resulted in twelve genetic loci being identified as co-localizing with hereditary MND. Six of these loci have had the genes associated with them identified. These are Copper-Zinc Superoxide dismutase 1 (SOD1), ALSIN, senataxin (SETX), vesicle associated membrane protein/synaptobrevin associated membrane protein (VABP), microtubule-associated protein tau (MAPT) and dynactin (DCTN1). Additionally, eight other genes, neurofilament heavy chain (NEFH), cytochrome C oxidase subunit 1 (CO1), vascular endothelial growth factor (VEGF), survival of motor neuron (SMN, or SMNT), survival of motor neuron 2 (SMN2), cilliary neurotrophic growth factor (CNTF), Apolipoprotein E ε4 (ApoEε4), solute carrier family 1 or glial high affinity glutamate transporter, member 2 (SLC1A2/EAAT2) and glutamate receptor 2 (GLUR2) have been identified as possible risk factors for sporadic MND. However, nearly every study that purports to show these risk factors has been challenged by other studies showing little or no correlation with MND.

The complexity of the genome and the difficulty in not only choosing which genes to test for variations but actually testing for the variations themselves is enormous. Many of the genes tentatively identified above as risk factors were selected by hunch and by accident. We feel that this task would be greatly simplified if there was a catalogue of genes that were most active in the spinal cord and more importantly in the motor neurons themselves. We are collecting these genes by the method of subtractive hybridization using other parts of the nervous system to subtract out spinal cord and motor neuron specific genes.