DNA is the foundational code for all proteins. The linear information held in DNA is “decoded” into linear strands of amino acids. These strands must then fold in a very precise, highly complex way to form proteins, each with distinct shapes and functions. When this folding goes awry, critical functions are lost or new, abnormal functions are gained, and renegade proteins can set off cascades of destruction, causing cells to malfunction and die. This was one of the earliest biological problems encountered by life on earth and the mechanism of building and folding proteins is shared from yeast to human.
Protein misfolding plays a key role in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). For each of the diseases, as the “culprit proteins” misfold, they damage nerve cells in various ways. The cellular stresses caused by protein misfolding lead to aggregation, or clumping, of proteins, which form sticky deposits in the brain cells themselves or in brain tissue. This results in nerve cell damage and, ultimately, cell death. Protein aggregation due to misfolding is an ancient cellular complication conserved across organisms from human brain cells to simple yeast cells. These biological parallels allow for the use of yeast as a model for neurodegenerative drug discovery, enabling unprecedented high-throughput screening for potential correcting compounds. Previous research and drug discovery efforts have been stymied by a lack of adequate tools to study the protein folding defects that are at the core of these diseases, which has slowed discovery endeavors for new drugs that will correct them.