Although amyotrophic lateral sclerosis (ALS) is one of the most common neuromuscular diseases worldwide, we know relatively little about its causes. Most ALS cases are sporadic, but research has focused on familial ALS (FALS) in a search for the genetic defects that underlie the disease. One such defect — mutations in the superoxide dismutase gene, SOD1 — occur in ∼20% of FALS cases. But FALS onset and severity can vary remarkably in families with the same SOD1 mutation. Now, Giess et al. report that additional mutations at CNTF — which encodes a potent motor-neuron survival factor — is probably one of several modifiers of ALS. Their findings indicate that, without the neuro-protective activity of CNTF, mutant SOD1 can trigger ALS earlier in both sporadic and familial patients, as well as in mice with mutant copies of both genes.

ALS is a rapidly progressive, invariably fatal neurological disease that attacks the neurons that control voluntary movement. It most commonly strikes between 40 and 60 years of age, but not always, as exemplified by the family studied by Giess et al. Three members of this family carry an exonic SOD1 mutation believed to disrupt SOD1 function. The mother developed ALS at 54; however, the son developed the disease at 25 and died 11 months later, while his sister remains unaffected at 35. Giess et al. genotyped CNTF in this family because of its previous association with ALS, and found that the son was homozygous null for CNTF, his mother heterozygous and his sister wild type. They also genotyped eight sporadic cases, who had an early onset of ALS, and who also proved to be CNTF−/−.

To check that this was not just a chance correlation, Giess et al. also studied motor-neuron survival in mice with mutations in both genes. As previous studies of ALS had indicated that mutant SOD1 acts as a dominant gain of function, the authors crossed transgenic mice (hSOD-1G93A) that overexpress a disease-associated, human mutant SOD1 with Cntf null mice. They found that hSOD-1G93A/Cntf−/− mice lose more lumbar spinal-cord motor neurons and have an earlier onset of disease than hSOD-1G93A/Cntf+/+ mice, but that disease duration is unchanged by Cntf loss. Linkage analysis showed that, although disease incidence is regulated by SOD1 in this cross, disease onset, when analysed as a quantitative trait, is controlled by Cntf.

One study has reported that 2% of healthy individuals are homozygous for a null CNTF mutation — indeed, the unaffected father of the proband reported here was CNTF+/− . Understanding how such mutations combine with other spontaneous, and perhaps epigenetic, events during life to give rise to sporadic neurodegenerative disease should fuel research for years to come.