Novel Interactions between Parkinson's Risk Genes and a-synuclein Reveal Disease Mechanisms and Pathway-Based Therapies

Overview

Objectives/Goals Parkinson's Disease (PD) is characterized by the death of dopaminergic (DA) neurons. The hallmark of PD is toxic aggregates of a-synuclein (a-syn) that induce degeneration of DA neurons. It is unclear how a-syn becomes toxic, which has hindered development of therapies. To elucidate PD, we studied its genetic forms, which provide insight into mechanisms of a-syn toxicity. We identified interactions between PD gene mutations and a-syn in yeast. The goals of our study were to 1) identify mechanisms of a-syn toxicity, and 2) identify potential therapies that target these pathways for treatment. Methods/Materials Deletions: We transformed yeast so that each strain contained a-syn and a PD gene deletion. Overexpressions: We transformed yeast so that each strain contained a PD gene overexpression and a-syn. Both: All yeast strains were grown as spotting assays. After growth, each strain was assigned a toxicity score to identify genes that enhanced or suppressed a-syn toxicity. Results Enhancers: Genes Swa2 and INP53 enhanced a-syn toxicity when deleted. Suppressors: Genes Sno4 and HSP31 suppressed toxicity when overexpressed. Conclusions/Discussion Enhancers: DA neurons fire after using vesicle recycling and ER->Golgi trafficking to transport dopamine. Swa2 and INP53 enable vesicle recycling, and a-syn inhibits ER->Golgi trafficking. Swa2 and INP53 may have enhanced toxicity because both mechanisms of vesicle trafficking were inhibited. Suppressors: Misfolded proteins cause oxidative stress, which damages cells. Neurons use chaperones to ensure proper folding. Sno4 and HSP31 are chaperones, and a-syn induces oxidative stress. Sno4 and HSP31 may have suppressed toxicity because the increased chaperones prevented oxidative stress. Validation of targets: We validated drugs that target these mechanisms. The compound curcumin promotes endocytosis, and nicotinamide prevents oxidative stress. Last year, we found that both compounds decreased toxic a-syn in C. elegans, confirming our results. Conclusions: 1) Novel PD mechanisms: i) Impaired vesicle recycling and ER->Golgi transport cause defects in synaptic vesicle trafficking/transmission, and ii) shortage of stress resistance chaperones causes oxidative stress due to misfolded protein accumulation. 2) Potential PD therapies: Treatments that i) promote vesicle trafficking, or ii) protect cells from misfolded proteins or oxidative stress.

Awards (1)

• Second Place

Competition history

• CSEF 2016 Toxicology · Entry S2107

Resources

• CSEF project summary ↗

Related projects

Closest projects by meaning, across every fair and year in the corpus.

Browse more like this

• All Biomedical and Health Sciences projects
• CSEF Biomedical and Health Sciences projects
• Every CSEF 2016 project
• CSEF Second Place winners