Abstract Protein quality control is essential to prevent the accumulation of proteotoxic species that cause neurodegenerative diseases. Therefore, understanding how cells respond to proteotoxic species is essential for developing therapies to treat these diseases. One class of proteins that are especially prone to aggregation are proteins with homopolymeric amino acid repeats, including polyglutamine repeats. Expanded polyglutamine repeats cause a class of nine neurodegenerative diseases and understanding how cells deal with long polyglutamine repeats will inform us about ways to treat the polyglutamine diseases and many other neurodegenerative diseases. My group has taken a unique approach to investigating how cells deal with long polyglutamine repeats. Instead of modeling polyglutamine repeats in organisms that have protein aggregation, we have identified the cellular slime mold Dictyostelium discoideum as being naturally resistant to polyglutamine aggregation. Dictyostelium is likely able to accomplish this due to the fact that this organism naturally encodes nearly 2,500 polyglutamine repeats with many surpassing the disease threshold in humans. Together this raises the question: What novel mechanisms do Dictyostelium utilize to suppress protein aggregation? Here we propose to begin to use a comparative biology-based approach to identify how Dictyostelium respond to cellular stressors that drive protein aggregation and neuronal death. These findings can then be utilized in human cells to determine if similar strategies can be used to enhance proteostasis and treat neurodegenerative diseases.