Yeast? Yes! A New Trend in Modeling Parkinson's Disease

By the end of this decade, the baby boomer generation will be progressing well into their 60s. As this aging population rises, so, too, will the incidence of age-related neurodegenerative diseases. The demand for geriatric care will begin to rise, putting a strain on healthcare for the elderly, space available in care facilities, and family members. These diseases such as Alzheimer’s, Parkinson’s, and amyotrophic lateral sclerosis (ALS or Lou Gherig’s Disease), are still all incurable and fatal diseases. Parkinson’s Disease (PD) is caused by the death of a specific set of midbrain neurons that control voluntary movement. The accumulation of a misfolded form of the αsynuclein protein into structures called Lewy Bodies may be one toxic agent involved in the pathogenesis of the disease. Four exciting new studies have modeled the misfolding of αsynuclein in yeast. Examining this protein in other cellular systems may shed light on its toxic effects, bringing researchers closer to finding a cure. In order to gain more insight into α-synuclein’s role in PD, the protein has been expressed in several model organisms, such as Drosophila, C. elegans, and mice (1). One recent model used for α-synuclein expression has been the simple, easily manipulated, eukaryotic organism, yeast. Although yeast cells are vastly different from brain cells, there are actually many similarities in the way both eukaryotic cells conduct protein folding process and the way they maintain quality control over their own proteins. Outeiro et al. first reported α-synuclein expression in baker’s yeast in 2003 (2), and the organism has since proven to be a widely used expression system. Three different laboratories have published their findings on α-synuclein expression in yeast in the two years thereafter. In comparing the most recent studies, much in vivo evidence is revealed about the protein’s lipid binding abilities, aggregation, and toxicity. Identifying α-synuclein’s localization in a eukaryotic cell such as yeast may suggest how the protein interacts in other eukaryotic cells, specifically neurons. Perhaps the most consistent finding among the studies has been the way in which α-synuclein localizes within baker’s yeast. Each group tagged α-synuclein to a green fluorescent protein (GFP) in order to visualize the localization of the protein within the cells. They observed that wild-type (WT) αsynuclein and the A53T familial mutant localized to the plasma membrane, while the A30P familial mutant was diffuse in the cytoplasm (3,4,5). This finding is consistent with a number of studies that have reported the protein’s lipid and membrane binding abilities. One group reported that a double A30P/A53T mutant displayed both membrane localization and diffuse cytoplasmic fluorescence (4). Two of these yeast studies found that by increasing expression time (3,5), the WT form of the protein lost membrane localization and accumulated within the cytoplasm. Determining the nature of this α-synuclein aggregation may give insight as to how the protein is involved in the pathogenesis of PD, a notion that is still not completely understood. In vitro studies have shown that αsynuclein aggregation is a nucleation-dependent process (6); that is, the protein will aggregate further if a seed of the