Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus

Amyotrophic lateral sclerosis (ALS) is a disease that leads to muscle weakness and paralysis. The symptoms become progressively worse over time to the point that patients die because they become unable to breathe. Over 170 different genetic mistakes (or mutations) in a gene that encodes a protein called SOD1 are known to cause ALS. These mutations cause the SOD1 protein to form different shapes that are toxic to nerve cells, leading to the gradual loss of the nerve cells that control movement. SOD1 is normally found in a compartment within nerve cells called the nucleus, which is where most of the cell’s genetic information is stored and managed. A nematode worm called Caenorhabditis elegans has often been used as a model to study the role of SOD1 in ALS because its nervous system shares many features in common with ours but is much smaller. Some evidence suggests that cells may be able to defend themselves against the harmful effects of abnormal SOD1 proteins. However, it is not clear how these defences might work. Zhong et al. examined variants of SOD1 proteins from human cells grown in a laboratory. The experiments show that some mutant SOD1 proteins fold in such a way that a small section of the protein that is normally buried within the protein’s structure is exposed on the surface. Mutant SOD1 proteins that expose this “peptide” are removed from the nucleus and are linked with faster progression of ALS in patients. Further experiments show that another protein called CRM1 can recognise this exposed peptide, leading to the removal of the mutant SOD1 proteins from the nucleus. Zhong et al. found that if mutant SOD1 is not removed from the nucleus of nerve cells, the nematode worms developed ALS symptoms even faster. These findings suggest that cells may be able to remove some mutant SOD1 proteins from the nucleus to defend themselves against the proteins’ toxic effects. Future work will reveal whether other cells use this approach to protect themselves against other diseases. The peptide discovered in this work may also have the potential to be used as a marker to predict how individual cases of ALS will progress, or as a target for treatments against the disease.