Modeling Neurodegenerative Diseases in S. cerevisiae

Neurodegenerative diseases (eg. Alzheimer’s disease) occur in humans primarily due to the misfolding of specific proteins as a result of genetic mutation. In the case of Alzheimer’s disease, the protein amyloid-ß misfolds... [ view full abstract ]

Neurodegenerative diseases (eg. Alzheimer’s disease) occur in humans primarily due to the misfolding of specific proteins as a result of genetic mutation. In the case of Alzheimer’s disease, the protein amyloid-ß misfolds such that hydrophobic residues shift to its exterior and multiple amyloid-ß molecules aggregate together to limit exposure of these residues to surrounding aqueous environment. The body’s capacity to tolerate such plaque accumulation weakens over time, and ultimately neurotoxicity occurs. A key thing to note is that protein aggregation is a hallmark across the protein misfolding pathologies associated with different disorders. So, as the demand for a treatment for neurodegeneration heightens in urgency, so does the speed and scale at which research of these pathologies occur. Here, we present a barcoded yeast screen, where each member of a yeast library contains a unique genetic barcode and expresses an aggregation prone protein associated with neurodegenerative disease under galactose induction. My work on this project was focused on building a second yeast library, where each member expresses a unique molecular chaperone from the yeast proteome. Members of the molecular chaperone library are screened against the entire barcoded yeast library by mating. If a molecular chaperone can correct some of the misfolding of AP proteins, we would expect one or several barcodes to get rescued in galactose-containing solution by sequencing and quantitative analysis. Experiments are still underway to test the efficacy of the various molecular chaperones, so no results can be reported as of yet.