Hydrophobic SOD Implicated in Lou Gehrig's Disease♦

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, causes degeneration of motor neurons in the spinal cord, brain stem, and brain resulting in muscle wasting and death. Approximately 20% of the familial cases of ALS are caused by mutations in the gene for Cu/Zn-superoxide dismutase (SOD1), an enzyme that normally catalyzes the dismutation of superoxide radicals to O₂ and H₂O₂. Although the cellular targets of mutant SOD1 are unknown, evidence suggests that misfolding or partial unfolding of mutant SOD1 proteins might be the cause of their toxicity.⇓

Increased hydrophobicity of SOD1 may contribute to aberrant interactions that promote toxicity in ALS.

In this Paper of the Week, Ashutosh Tiwari and colleagues provide a plausible explanation for the common physicochemical defect in the 100 or so SOD1 mutations that cause ALS. The mutant proteins appear to become abnormally hydrophobic under conditions that impair metal binding and produce locally destabilized electrostatic and zinc binding loops. The abnormal hydrophobicity may then promote aberrant interactions of the enzyme with itself or with other cellular constituents to produce the toxicity associated with ALS. This paper clearly illustrates how this may be possible in the case of mutant SOD1 and presents useful techniques that may be applied to the study of other aggregating proteins involved in neurodegenerative disease.