1. A High-Throughput Screening Platform for the Identification of Novel Pharmacoperones for SOD1-linked Familial ALS

Karun Salvady University of Texas - Austin
Faculty Sponsor(s): Mark Henderson Not Affiliated with a College/University
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects both lower motor neurons in the brainstem and spinal cord and upper motor neurons in the motor cortex. Degeneration of these
neurons leads to muscle atrophy and weakness, fasciculations, spasticity,
and death within 3-5 years from the onset of symptoms. There are only two
FDA-approved pharmaceuticals for ALS (Riluzole and Edaravone) both of
which have mild effects, demanding the development of a new therapeutic.
Approximately 10% of all ALS cases are familial and about 20% of
these cases are caused by mutations of the copper-zinc superoxide
dismutase 1 (SOD1) enzyme. Over one hundred eighty mutations in SOD1,
dispersed across the entire protein, have been linked to selective motor
neuron death in ALS. A common feature of many SOD1 mutations is
transition to a toxic conformation, which is caused by destabilization and
aggregation of the protein. Abnormal accumulation of such proteins in motor
neurons is a pathological hallmark in SOD1-related familial ALS. Therefore,
stabilization of SOD1 structure and restoration to its wild-type conformation
could provide a treatment approach for SOD1-linked ALS. In the past,
chemical chaperones have been successfully implemented to stabilize and
refold certain disease-causing misfolded proteins, and two have been
approved by the FDA for clinical applications. However, no chemical
chaperone to induce SOD1 refolding has made significant progress in the
drug discovery pipeline, despite the tremendous potential of such
chaperones as effective therapeutics for ALS. Recent work in the Fang lab
identified a common feature of misfolded SOD1 variants, whereby a normally
buried region of the protein is exposed and functions as a nuclear export
sequence (NES). Using the nuclear export phenotype of misfolded SOD1,
we developed a high-throughput screening approach to identify small
molecules that promote refolding of SOD1 mutants.
Poster Presentation

When & Where

Irwin Library 3rd Floor