Protein misfolding toxicity is a major factor in neurological disease. The high load of misfolded proteins in tumors has also been called cancer’s ‘Achilles heel.’ But to understand how misfolded proteins impact health, we need to quantify how cell fitness declines as misfolded proteins accumulate. One common hypothesis as to why misfolded proteins are toxic is that they steal resources, implying toxicity depends on the availability of resources such as chaperones. Our goal is to make accurate predictions about the context-dependent costs of misfolding mutations by quantifying the relationship between the number of misfolded proteins in a cell and cell fitness. However, we recently found that this relationship may differ even for different misfolded variants of the same protein! We study the effects of misfolding on cells through a combination of novel methods, some of which utilize DNA barcodes and CRISPR gene-editing, some of which hunt for subpopulations of cells that are particularly sensitive to misfolding, and some of which involve technologies that we developed ourselves. Deciphering the relationship between cell health and protein misfolding will reveal when and how these extremely common, but typically small-effect, mutations contribute to evolutionary processes.

Relevant Papers:
-Fitness costs do not necessarily scale with the degree of protein misfolding link
-A novel system to identify mutations that cause protein misfolding link
-Our review of mechanistic hypotheses underlying context-dependence link
-Quantifying the toxicity of misfolded proteins link