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.
Original language | English (US) |
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Pages (from-to) | 87-96 |
Number of pages | 10 |
Journal | Amyotrophic Lateral Sclerosis |
Volume | 12 |
Issue number | 2 |
DOIs | |
State | Published - Mar 2011 |
Funding
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.
Keywords
- ALS therapy
- high throughput screening
- protein aggregation
ASJC Scopus subject areas
- Clinical Neurology
- Neurology