In 1939, after playing 2,130 consec-utive games at first base for the New York Yankees, Lou Gehrig missed a game. Two years later, at the age of 37, he was dead. Lou Gehrig’s disease, or amyotrophic lateral sclerosis (ALS), afflicts 35,000 Americans. Similar to Alzheimer’s disease (AD) and Parkinson’s disease (PD), ALS is a late-onset neurodegenerative disease characterized by protein aggregates that colocalize with neuronal loss (1, 2). Unlike AD and PD, ALS progresses very rapidly, and most patients die within 5 years of diagnosis, often from asphyxia. There is no effective treatment. However, an article in this issue of the PNAS (3), taken together with a recent article from our laboratory (4), suggests a therapeutic target and offers hope that this situation could soon change. We imagine that the progression of ALS could be significantly slowed by a drug that would prevent aggregation of a ubiquitous enzyme.

In 10% of cases, ALS is transmitted in an autosomal-dominant manner [familial ALS (FALS)](5, 6). The most commonly mutated gene, accounting for 20% of all FALS, encodes superoxide dismutase type 1 (SOD1), a dimeric metalloenzyme that is rich in ß-sheet structure and contains copper-and zincbinding sites, the former being critical for catalysis (Fig. 1). FALS has been linked to 100 SOD1 mutations, which are scattered throughout the threedimensional structure (7). The A4V mutation has been frequently studied because it produces a rapidly progressing form of FALS, suggesting that its pathogenic properties may be observ-