Motor neuron disease, or amyotrophic lateral sclerosis (ALS), is a disorder
characterised by progressive weakness and atrophy of skeletal muscles, caused by
the selective loss of motor neurons. It occurs in both familial and sporadic forms.
Although the genetic basis of the disease in a minority of cases has been identified,
the precise molecular mechanism underlying the disease remains to be elucidated.
There is a range of mouse mutants which model the disease. These mouse models,
both classical and transgenic, have been particularly valuable in providing clues to
the pathogenesis of the disease. One such mutant is wasted, in which the mice
develop a progressive neuromuscular phenotype from 21 days of age. They
deteriorate quickly, and die by 28 days. The genetic defect responsible for wasted is
a 15kb deletion which leads to the abolition of the expression of eukaryotic
elongation factor 1 A-2 (eEFlA-2). This is a tissue-specific isoform, apparently
unique to mammals, of the more widely expressed eEFl A-l. In this PhD thesis I
describe the further characterisation of wasted as a model for ALS, using
immunohistochemistry to evaluate the similarities between the phenotype ofwasted
mice and that ofALS patients. I have also screened the human gene, EEF1A2, for
mutations in both familial and sporadic patients. Although there were polymorphisms
within the gene which were also present in healthy controls, there were no mutations.
It is thus unlikely that mutations in EEF1A2 are responsible for anything other than
rare cases of ALS. I have designed and generated anti-peptide antibodies against
eEFlA-l and eEFlA-2 which I have shown to be isoform-specific. These were used
to study the expression of the two isoforms in mouse tissues. I have also shown that
the African clawed frog, Xenopus laevis, has a developmentally-regulated, tissuespecific isoform homologous to eEFl A-2.