eEF1A2 and neuronal degeneration

Abstract

Translation elongation factor eEF1A (eukaryotic elongation factor 1A) exists as two individually encoded variants in mammals, which are 98% similar and 92% identical at the amino acid level. One variant, eEF1A1, is almost ubiquitously expressed, the other variant, eEF1A2, shows a very restricted pattern of expression. A spontaneous mutation was described in 1972, which gives rise to the wasted phenotype: homozygous wst/wst mice develop normally until shortly after weaning, but then lose muscle bulk, acquire tremors and gait abnormalities and die by 4 weeks. This mutation has been shown to be a deletion of 15 kb that removes the promoter and first exon of the gene encoding eEF1A2. The reciprocal pattern of expression of eEF1A1 and eEF1A2 in muscle fits well with the timing of onset of the phenotype of wasted mice: eEF1A1 declines after birth until it is undetectable by 3 weeks, whereas eEF1A2 expression increases over this time. No other gene is present in the wasted deletion, and transgenic studies have shown that the phenotype is due to loss of eEF1A2. We have shown that eEF1A2, but not eEF1A1, is also expressed at high levels in motor neurons in the spinal cord. Wasted mice develop many pathological features of motor neuron degeneration and may represent a good model for early onset of motor neuron disease. Molecular modelling of the eEF1A1 and eEF1A2 protein structures highlights differences between the two variants that may be critical for functional differences. Interactions between eEF1A2 and ZPR1 (zinc-finger protein 1), which interacts with the SMN (survival motor neuron) protein, may be important in motor neuron biology.

Translation elongation factor-1A1 (eEF1A1) localizes to the spine by domain III

“…It is noteworthy that the cell types that switch off eEF1A1 tend to be those that have a strong, stable cytoskeletal organization, such as neurons and muscle. Therefore, Abbott et al (35) raised a hypothesis that these cell types need to switch off eEF1A1 to prevent or modify the cytoskeletal rearranging properties, but for the obvious need to maintain protein synthesis, they use eEF1A2. Supporting this hypothesis, muscle cells switch eEF1A1 back on in response to denervation or toxic injury, reverting back to high levels of eEF1A2 after recovery (36,37).…”

EEF1A1 (eukaryotic translation elongation factor 1 alpha 1)

“…No other gene is present in the wasted deletion, and transgenic studies have shown that the EEF1A1 (eukaryotic translation elongation factor 1 alpha 1) Scaggiante B, Bosutti A Atlas Genet Cytogenet Oncol Haematol. 2015;19(4) phenotype is due to loss of eEF1A2 translation activity in muscle (Doig et al, 2013;Abbott et al, 2009). In neuronal cells, an eEF1A1 interaction with the yeast two-hybrid protein K (HYPK), highlights the involvement of HYPK in the regulation of cell growth, cell cycle, unfolded protein response and cell death.…”

Gene Expression in Neuronal Disease

“…The extensive roles that translation factors including eIF2B (eukaryotic initiation factor 2B), which is mutated in VWM/CACH, play in learning and memory was also highlighted. Abbott et al [8] showed that loss of a translation elongation factor, eEF1A2 (eukaryotic elongation factor 1A2), causes motor neuron degeneration in mice, providing a good model for motor neuron disease. Expression of eEF1A2 is highly restricted compared with the more ubiquitous eEF1A1, and fits well with the onset of the phenotype.…”

“…The final stage in the gene to protein path is translation and Abbott et al [8] (pp. 1293-1297) and Pavitt and Proud [9] (pp.…”