Motoneurons buckling under stress

Amyotrophic lateral sclerosis (ALS) selectively affects motoneurons. This selectivity is seen even for certain familial cases of ALS (fALS) that are caused by mutations in a ubiquitously expressed gene, SOD1, which codes for a superoxide dismutase enzyme that is important for cells' antioxidant defenses. Pico Caroni's laboratory previously found that, in mice expressing the human fALS mutation SOD1^G93A, the fast fatigable (FF) motoneurons die early during the course of the disease, whereas the fast fatigue–resistant (FFR) motoneurons survive longer and the slow motoneurons are largely resistant to degeneration.

On pp. 627–636 of this issue, Saxena et al. studied gene expression patterns in hopes of understanding why FF motoneurons are particularly prone to degeneration. Because FF, FFR and slow motoneurons selectively innervate particular muscles, the authors were able to separately label FF cells and a mixed FFR/slow population using retrograde tracers. The two sets of neurons were laser-microdissected from wild-type and SOD1^G93A transgenic mice at several time points preceding the onset of axonal loss. Microarray analysis revealed the expression of stress indicators in 12-d-old FF motoneurons. At 32 d of age, genes involved in the unfolded protein response (UPR) were strongly upregulated. The UPR preceded the initial loss of peripheral FF axons by about 20 d. Very similar patterns of stress and UPR gene induction, preceding denervation by 20–30 d, were seen in FF motoneurons from two other SOD1 mutant transgenic fALS model mouse lines.

All cells in the SOD1^G93A mice express high levels of mutant, misfolding SOD1 protein. Both vulnerable and resistant motoneurons (but not other cells in the spinal cord) similarly accumulated ubiquitinated misfolded protein over time. In the vulnerable FF motoneurons, this accumulation was followed by the induction of UPR genes within a few days. A subgroup of the resistant population upregulated UPR genes approximately 4 weeks later, followed by axon degeneration another 4 weeks after that. The figure here shows a section of lumbar spinal cord from a 55-d-old SOD1^G93A mouse. Highly vulnerable motoneurons strongly express the UPR marker phospho-eIF2α (green). Resistant motoneurons at this age also show signs of endoplasmic reticulum stress, indicated by immunostaining for BiP (red), but do not yet express UPR genes.

Although the authors' analysis does not explain why FF motoneurons are so particularly vulnerable to damage by mutant SOD1, this careful longitudinal analysis of gene expression patterns pinpoints what seems to be a watershed mechanism: the induction of the UPR genes. Future work will look into the exact regulation of UPR genes and will hopefully reveal the reason for selective motoneuron vulnerability in ALS.