A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.

Sangwan, S.; Rieder, H.; Moore, D.; Khanlou, N.; Novitch, B.; Geisberg, M.; Eisenberg, D.

doi:10.1101/2025.05.05.652290

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bioRxiv · 10.1101/2025.05.05.652290

A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.

Sangwan, S.·Rieder, H.·Moore, D.·Khanlou, N.·Novitch, B.·Geisberg, M.·Eisenberg, D.

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Abstract

Antibodies offer versatility as diagnostic and therapeutic tools to target specific protein epitopes. However, the transient nature of intermediate protein conformations, such as that of amyloid oligomers, poses a challenge for antibody development. We use a structure-guided approach to generate a monoclonal antibody against oligomers of Superoxide Dismutase 1 (SOD1). Mutations in SOD1 are linked to a subset of familial Amyotrophic Lateral Sclerosis (fALS), a fatal neurodegenerative disease. Based on the corkscrew-like features of non-native SOD1 oligomers previously determined, we generate an antibody specific to SOD1 oligomers. We show that the antibody, CSAb detects SOD1 oligomers, not fibrils or native SOD1, and alleviates the cytotoxic effects of SOD1 oligomers in a cell culture model of primary motor neurons. Immunohistochemical analyses of human ALS subjects show CSAb reactivity in both neuronal and non-neuronal cells. Finally, we provide evidence that CSAb reactive SOD1 oligomers are present in non-SOD1 linked fALS and sporadic ALS subjects. Together, our study provides a new probe against SOD1 oligomers and suggests that cytotoxic SOD1 oligomers are prevalent in diverse ALS genotypes.

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Sangwan, S., Rieder, H., Moore, D., Khanlou, N., Novitch, B., Geisberg, M., Eisenberg, D.. 2025-05-08. A structure-guided antibody detects SOD1 oligomers in diverse ALS genotypes.. https://doi.org/10.1101/2025.05.05.652290

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