Identification of compounds protective against G93A-SOD1 toxicity for the treatment of amyotrophic lateral sclerosis

Abstract

The underlying cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disorder, remains unknown. However, there is strong evidence that one pathophysiological mechanism, toxic protein misfolding and/or aggregation, may trigger motor neuron dysfunction and loss. Since the clinical and pathological features of sporadic and familial ALS are indistinguishable, all forms of the disease may be better understood and ultimately treated by studying pathogenesis and therapy in models expressing mutant forms of SOD1. We developed a cellular model in which cell death depended on the expression of G93A-SOD1, a mutant form of superoxide dismutase found in familial ALS patients that produces toxic protein aggregates. This cellular model was optimized for high throughput screening to identify protective compounds from a >50,000 member chemical library. Three novel chemical scaffolds were selected for further study following screen implementation, counter-screening and secondary testing, including studies with purchased analogs. All three scaffolds blocked SOD1 aggregation in high content screening assays and data on the optimization and further characterization of these compounds will be reported separately. These data suggest that optimization of these chemicals scaffolds may produce therapeutic candidates for ALS patients.

Key words::

• ALS therapy
• protein aggregation
• high throughput screening

Acknowledgements

This work was supported by grants from the National Institutes of Health, the ALS Association (TREAT program), Department of Defense (Grant AL093052) and the Veterans Administration at the Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts.

Declaration of interest: The authors have had no involvements that might raise a question of bias in the work reported or in the conclusions, implications or opinions stated.