Image: Mattias Pettersson
Image: Mattias Pettersson
Research group 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.
Helena Alstermark, Ani Minasian, Stefan Marklund (group leader), Laura Leykam, Karin Hjertkvist, Per Zetterström (group leader), Eva Jonsson, Caitlin Henne and Agneta Öberg in the lab.
Image Mattias Pettersson
Per Zetterström, group leader, and Karin Hjertkvist, biomedical analyst, are looking at the enzymatic activity of SOD1 measured in a sample of blood or spinal fluid.
Image Mattias Pettersson
Ani Minasian, research engineer, is loading protein samples in a polyacrylamide gel for size separation by electrophoresis before Western blot analysis.
Image Mattias Pettersson
Laura Leykam, PhD-student, isolates misfolded and aggregated SOD1 protein using magnetic beads, also known as microbeads, conjugated to specific antibodies.
Image Mattias Pettersson
Caitlin Henne, PhD-student, is transfering samples to an ELISA-plate for measurements of misfolded SOD1 protein.
Image Mattias Pettersson
Helena Alstermark, research engineer, is looking at samples analysed by dot blot.
Image Mattias Pettersson
Agneta Öberg, laboratory assistant, is placing samples in the centrifuge.
Image Mattias PetterssonAmyotrophic 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.
