DISCOVERIES SHOULD AID RESEARCH INTO CAUSE OF ALS
Two teams of researchers at Northwestern University have found a novel pathological hallmark of the
neurodegenerative disease amyotrophic lateral sclerosis (ALS) at the molecular level. The neurologists and
biochemists show how and why the mutated superoxide dismutase (SOD1) protein, which is associated with
a familial form of ALS, becomes vulnerable and prone to aggregation and also provide evidence linking
disease onset with the formation of intermolecular aggregates.
The findings, which have implications for new therapeutics for the devastating disease, were published
online this week in two related papers by the Proceedings of the National Academy of Sciences (PNAS).
ALS is a progressive paralytic disorder caused by degeneration of motor neurons in the brain and spinal
cord. The cause and development (pathogenesis) of the fatal disease are not known, and there is no effective
treatment. Fifteen years ago, an international consortium led by Teepu Siddique, M.D., Les Turner ALS
Foundation/Herbert C. Wenske Foundation Professor at Northwestern’s Feinberg School of Medicine,
mapped the first ALS gene to chromosome 21. Subsequently, they found that mutations in the SOD1 gene
are responsible for 20 percent of familial (inherited) ALS cases. Siddique and his colleagues also made the
first ALS transgenic mouse models.
Although more than 100 types of a single mutation in the SOD1 gene have been identified and multiple
lines of the mouse models developed, a key question remains to be answered: How does the genetic
mutation alter this incredibly stable protein to make it so toxic that it kills motor neurons and causes
The presence of aggregated proteins is common to many neurodegenerative disorders, including ALS
and Alzheimer’s, Parkinson’s and prion diseases, but the relevance of these aggregates to the diseases is not
well understood. In ALS patients with SOD1 mutations and mouse models overexpressing mut