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α-synuclein budding yeast model

Toxicity enhanced by impaired proteasome and oxidative stress

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Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder that results from the selective loss of midbrain dopaminergic neurons. Misfolding and aggregation of the protein α-synuclein, oxidative damage, and proteasomal impairment are all hypotheses for the molecular cause of this selective neurotoxicity. Here, we describe a Saccharomyces cerevisiae model to evaluate the misfolding, aggregation, and toxicity-inducing ability of wild-type α-synuclein and three mutants (A30P, A53T, and A30P/A53T), and we compare regulation of these properties by dysfunctional proteasomes and by oxidative stress. We found prominent localization of wild-type and A53T α-synuclein near the plasma membrane, supporting known in vitro lipid-binding ability. In contrast, A30P was mostly cytoplasmic, whereas A30P/A53T displayed both types of fluorescence. Surprisingly, α-synuclein was not toxic to several yeast strains tested. When yeast mutants for the proteasomal barrel (doa3-1) were evaluated, delayed α-synuclein synthesis and membrane association were observed; yeast mutant for the proteasomal cap (sen3-1) exhibited increased accumulation and aggregation of α-synuclein. Both sen3-1 and doa3-1 mutants exhibited synthetic lethality with α-synuclein. When yeasts were challenged with an oxidant (hydrogen peroxide), α-synuclein was extremely lethal to cells that lacked managanese superoxide dismutase Mn-SOD (sod2Δ) but not to cells that lacked copper, zinc superoxide dismutase Cu,Zn-SOD (sod1Δ). Despite the toxicity, sod2Δ cells never displayed intracellular aggregates of α-synuclein. We suggest that the toxic α-synuclein species in yeast are smaller than the visible aggregates, and toxicity might involve α-synuclein membrane association. Thus, yeasts have emerged effective organisms for characterizing factors and mechanisms that regulate α-synuclein toxicity.

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  1. Biology Department, Lake Forest College, 60045, Lake Forest, IL

    Nijee Sharma, Katrina A. Brandis, Sara K. Herrera, Brandon E. Johnson, Tulaza Vaidya, Ruja Shrestha & Shubhik K. DebBurman

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  1. Nijee Sharma
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Sharma, N., Brandis, K.A., Herrera, S.K. et al. α-synuclein budding yeast model. J Mol Neurosci 28, 161–178 (2006). https://doi.org/10.1385/JMN:28:2:161

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