Since 1993 we have closely studied the biochemical properties of SOD1 and how it causes ALS. Our focus is on how mutations in SOD1 leads to misfolding of the three-dimensional structure of the protein, giving it pathogenic qualities, and how the disease-causing form can spread between cells.
Amyotrophic lateral sclerosis (ALS) is characterized by adult-onset degeneration of the upper and lower motor neurons. The disease begins focally and then spreads contiguously, resulting in spreading paralysis and finally death from respiratory failure usually within a few years.
A major known cause of the disease is mutations in the gene encoding superoxide dismutase-1 (SOD1) which confer a toxic gain of function which has been poorly understood. Neuronal inclusions containing aggregated SOD1 are hallmarks of ALS, both in patients and in transgenic animal models expressing mutant human SOD1s.
We have developed a new method, "binary epitope mapping", for analysis of the molecular structure of protein aggregates. Using it we have found the two strains of SOD1 aggregates, A and B, can arise in the CNS. We have now shown that inoculation of minute amounts of A and B aggregates into lumbar spinal cord of mice causes a premature fatal ALS-like disease. Concomitantly, exponentially growing strain A and B aggregations, respectively, propagate throughout the spinal cord and brain stem. The A and B SOD1 aggregates are thus prions which transmit templated spreading SOD1 aggregation and ALS.
We are testing inoculations of the A and B prions in mice expressing several different mutant SOD1s to search for prion transmission barriers. The ability of the prions to transmit disease from various sites of inoculation is examined. Treatment attempts are made with antibodies reactive with accessible epitopes on the prions.