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Leveraging Natural Variation and Yeast Genetics for Novel Insights on the Molecular Basis of Cytotoxicity for Parkinson's Related Protein alpha-Synuclein

ABSTRACT: Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting more than 5 million people worldwide. A hallmark of PD is dopaminergic neuronal cell death caused by cytotoxic aggregates of alpha-synuclein (a-syn). However, it is unclear why a-syn forms cytotoxic aggregates in some individuals but not others, and how these a-syn aggregates cause cellular toxicity. Understanding the genetic basis of variation in a-syn cytotoxicity in humans is challenging, so we turned to the budding yeast Saccharomyces cerevisiae as a powerful and tractable genetic model. a-Syn overexpression in yeast recapitulates the subcellular localization and cytotoxicity seen in neuronal cells, and, excitingly, we have identified wild yeast strains with either increased susceptibility or high resistance to a-syn overexpression. Thus, we have a new model for understanding the genetic basis of natural variation in a-syn susceptibility. Using a panel of strains with high or low a-syn susceptibility, we have performed global transcriptional profiling following over-expression of a-syn using two different promoter systems. Our results suggest that strains with natural resistance to a-syn over-expression have a more robust gene expression response, while also identifying candidate genes that protect against a-syn toxicity or exacerbate it. Overall, this work demonstrates the power of using natural variation combined with system genetics to identify novel genes and processes important for disease susceptibility.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE296747 | GEO | 2025/12/24

REPOSITORIES: GEO

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Project description:Lactic acid bacteria confer a variety of health benefits. Here we investigate the mechanisms by which Lactobacillus brevis KB290 enhances cell-mediated cytotoxic activity. We fed a diet containing KB290 (3 M-CM-^W 10^9 colony-forming units/g) , or potato starch, to 9-week-old female BALB/c mice for 1, 4, 7, or 14 days and examined the cytotoxic activity of splenocytes was measured. RNA was extracted from the spleen and analyzed for gene expression by DNA microarray. KB290 enhanced the cell-mediated cytotoxic activity of splenocytes. The Gene Ontology (GO) terms related to immune process were significantly enriched in up-regulated gene set for 7 days and the GO terms related to cellular process were enriched in down-regulated gene set on days 4 and 7. Among the GO terms related to immune process, positive regulation of T cell-mediated cytotoxicity was existed. Almost all of the genes included in the term encoded MHC class I molecules, which are involved in the presentation of antigen to CD8+ cytotoxic T cells. On the other hand, the over-represented Kyoto Encyclopedia of Genes and Genomes pathways among the up-regulated genes were those for natural killer cell-mediated cytotoxicity and antigen processing and presentation on day 1. Although the up-regulated genes involved in antigen processing and presentation for stimulation of CD8+ cytotoxic T cells were not observed on day 14, some genes involved in T cell and natural killer cell activation remained up-regulated until day 14. The sequential gene expression profiling reflected the changes in cytotoxic activity during KB290 feeding. These results suggest that the enhanced cytotoxic activity could have been caused both by activation of natural killer cells and by CD8+ cytotoxic T cells stimulated via MHC class I presentation. Specific-pathogen-free female BALB/c mice, aged 8 weeks, were purchased from Charles River Laboratories Japan, Inc. They (n = 48) were divided into two groups, control and KB290 (4 cages per group) with equal mean body weights. They were allowed to free access to a commercial normal diet CE-2 (CLEA Japan, Inc.) and sterile water during one-week acclimation period. Then, they received lyophilized KB290 for the treatment group diet (3x109 cfu/g) or 5.8% (w/w) potato starch (Nippon Starch Chemical) for the control group diet for 1, 4, 7, and 14 days. Daily intake of KB290 containing diet per treated mouse was 3.99g, or about 1 M-CM-^W 1010 cfu. On day 1, 4, 7, and 14, six mice in each group were euthanized and their spleens were sampled for Cell-mediated cytotoxicity and DNA microarray assay.

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Leveraging Natural Variation and Yeast Genetics for Novel Insights on the Molecular Basis of Cytotoxicity for Parkinson's Related Protein alpha-Synuclein

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