Amyotrophic Lateral Sclerosis (ALS) is an age-dependent, devastating disease for which there is no cure. Understanding the mechanisms of cell death that underlie ALS pathology is therefore of great importance. Our paper provides a possible new mechanistic insight into the pathogenesis of a familial form of the disease. We described an unsuspected link between the mutant SOD1 protein (mutations in SOD1 cause disease in a subset of familial ALS patients) and one of the most important inhibitors of cell death, the Bcl-2 protein. Perhaps, the mutant SOD1 protein initiates motor neuron death by binding with Bcl-2 to form protein clumps that stick to mitochondria.

The paper describes a surprising mechanism by which mutant SOD1 protein binds to Bcl-2 and suggests a novel toxic function of mutant SOD1 in ALS pathogenesis.

In a subset of familial ALS patients, mutations in the SOD1 gene cause this motor neuron disease. We do not know all of the mechanisms by which the mutated SOD1 kills motor neurons. What we do know is that mutations convert normal SOD1, usually a survival protein, into a toxic molecule. In our paper, we show that the malformed, toxic mutant SOD1 protein binds to Bcl-2. In this view, Bcl-2 can become a hostage or an accomplice of the mutant SOD1. As a hostage, it cannot protect the motor neurons against death any longer. As an accomplice, it may turn itself into a toxic protein when linked to mutant SOD1. In the latter case, two normally protective proteins may, together, become killers. Understanding how the mutant SOD1 protein kills motor neurons is fundamental for the development of new therapies for SOD1-mediated ALS. Our paper provides new insights into these mechanisms.

In 1993, a collaborative group directed by Dr. Brown and others made the breakthrough discovery that mutations in SOD1 cause one form of ALS. Since then, the laboratory has been investigating the mechanisms by which the mutant SOD1 proteins are toxic to motor neurons. The findings described in our paper represent a new step in this ongoing process.

ALS is an untreatable disease. The first step in devising new treatments is to understand the molecular pathogenesis of motor neuron death. Because it describes a new, putative mechanism of cell death in SOD1-related ALS, our paper may represent a step toward new treatments. However, a major caveat is that SOD1-mediated ALS represents 2-3% of all ALS; it remains to be determined whether the adverse interaction of mutant SOD1 and Bcl-2 is relevant to other types of ALS.