The endoplasmic reticulum (ER) plays an important role in calcium storage as well as in calcium signalling. Disturbances in ER calcium homeostasis inhibit the normal folding and processing of newly synthesized proteins. In addition, gene mutations affecting protein conformation can result in an accumulation of unfolded proteins in the ER. This leads to ER stress and induces the unfolded protein response (UPR) characterized by an inhibition of protein synthesis and an induction of ER-resident chaperones (Paschen & Mengesdorf, 2005).

Both a disturbance in calcium metabolism and an upregulation of the UPR are associated with amyotrophic lateral sclerosis (ALS). In ALS, motoneurons degenerate and the selectivity of this process has been linked to the special way these cells handle calcium (Van Den Bosch et al., 2006). In addition, vulnerable motoneurons are prone to enhanced ER stress (Saxena et al., 2009). Considerable evidence is available that markers for the UPR are increased in cell lines (Atkin et al., 2006), in transgenic animals (Atkin et al., 2006; Kikuchi et al., 2006) and in sporadic ALS patients (Ilieva et al., 2007; Atkin et al., 2008).

In this issue’s Featured Article by Prell et al. (2012), the presence of a number of UPR markers is reported for the first time in purified motoneurons isolated from transgenic mice overexpressing mutant superoxide dismutase 1 (SOD1). Mutations in SOD1 are a prevalent genetic cause of familial ALS and the transgenic mouse model shows the same age-dependent degeneration of motoneurons as observed in patients. Prell et al. cultured primary motoneurons on a glial feeder layer and showed a marked activation of the basic leucine-zipper transcription factor 6 (ATF6α), splicing of X-box binding protein 1 (XBP1) and phosphorylation of the eukaryotic initiation factor 2 (eIF2α). Basal levels of these three markers were higher in motoneurons from mutant SOD1 mice than from wild-type mice and, after imposing additional ER stress by emptying the calcium stores, a prolonged and stronger activation of the UPR was observed. The attractiveness of the cell culture system used by Prell et al. is that mutant SOD1-containing motoneurons can be combined with glial feeder layers from wild-type mice and vice versa. By doing so, it was discovered that the ER stress is a genuine feature of mutant SOD1-containing motoneurons and that the glial feeder layer does not play a role in this process. Another advantage of this co-culture system is that it can be used to screen for compounds that counteract UPR induction. That such a strategy might work is indicated by the positive results obtained after treating mutant SOD1 mice with salubrinal, a selective inhibitor of eIF2α (Saxena et al., 2009).

In conclusion, the study by Prell et al. (2012) provides additional evidence for the involvement in ALS of ER stress linked to the ER–mitochondrial calcium cycle. In addition, this study opens perspectives for the search for drugs that influence these processes and that could have therapeutic potential for the treatment of ALS.


  1. Top of page
  2. References
  • Atkin, J.D., Farg, M.A., Turner, B.J., Tomas, D., Lysaght, J.A., Nunan, J., Rembach, A., Nagley, P., Beart, P.M., Cheema, S.S. & Horne, M.K. (2006) Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1. J. Biol. Chem., 281, 3015230165.
  • Atkin, J.D., Farg, M.A., Walker, A.K., McLean, C., Tomas, D. & Horne, M.K. (2008) Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol. Dis., 30, 400407.
  • Ilieva, E.V., Ayala, V., Jové, M., Dalfó, E., Cacabelos, D., Povedano, M., Bellmunt, M.J., Ferrer, I., Pamplona, R. & Portero-Otín, M. (2007) Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis. Brain, 130, 31113123.
  • Kikuchi, H., Almer, G., Yamashita, S., Guégan, C., Nagai, M., Xu, Z., Sosunov, A.A., McKhann, G.M. II & Przedborski, S. (2006) Spinal cord endoplasmic reticulum stress associated with a microsomal accumulation of mutant superoxide dismutase-1 in an ALS model. Proc. Natl. Acad. Sci. USA, 103, 60256030.
  • Paschen, W. & Mengesdorf, T. (2005) Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium, 38, 409415.
  • Prell, T., Lautenschläger, J., Witte, O.W., Carri, M.T. & Grosskreutz, J. (2012) The unfolded protein response in models of human mutant G93A amyotrophic lateral sclerosis. Eur. J. Neurosci., 35, 654663.
  • Saxena, S., Cabuy, E. & Caroni, P. (2009) A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat. Neurosci., 12, 627636.
  • Van Den Bosch, L., Van Damme, P., Bogaert, E. & Robberecht, W. (2006) The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim. Biophys. Acta, 1762, 10681082.