Abstract

Misfolding of Cu/Zn-superoxide dismutase (SOD1) is emerging as a mechanism underlying motor neuron degeneration in individuals with amyotrophic lateral sclerosis (ALS) who carry a mutant SOD1 gene (SOD1 ALS). Here we describe a structure-guided approach to developing an antibody that specifically recognizes monomer-misfolded forms of SOD1. We raised this antibody to an epitope that is normally buried in the SOD1 native homodimer interface. The SOD1 exposed dimer interface (SEDI) antibody recognizes only those SOD1 conformations in which the native dimer is disrupted or misfolded and thereby exposes the hydrophobic dimer interface. Using the SEDI antibody, we established the presence of monomer-misfolded SOD1 in three ALS mouse models, with G37R, G85R and G93A SOD1 mutations, and in a human individual with an A4V SOD1 mutation. Despite ubiquitous expression, misfolded SOD1 was found primarily within degenerating motor neurons. Misfolded SOD1 appeared before the onset of symptoms and decreased at the end stage of the disease, concomitant with motor neuron loss.

1. Departments of Biochemistry and Medical Biophysics, University of Toronto and Ontario Cancer Institute, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
2. Centre for Research in Neurodegenerative Diseases, and Department of Laboratory Medicine and Pathobiology, University of Toronto, 6 Queen's Park Crescent West, Toronto, Ontario M5S 3H2, Canada.
3. Ludwig Institute for Cancer Research and University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
4. Present address: Department of Medicine (Neurology) and Brain Research Centre, University of British Columbia Hospital, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada.

Correspondence to: Avijit Chakrabartty¹ e-mail: chakrab@uhnres.utoronto.ca

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