Apoptosis, Induced by Human α-Synuclein in Yeast, Can Occur Independent of Functional Mitochondria.

Human α-synuclein expression in baker's yeast reportedly induces mitochondria-dependent apoptosis. Surprisingly, we find that, under de-repressing conditions of the inducible promoters, yeast cells expressing chromosomally-integrated copies of the human α-synuclein gene are not killed, but spontaneously form respiration-deficient rho-minus (ρ) petites. Although yeast cells can undergo cell death (apoptosis) from loss of mitochondrial function, they can also survive without functional mitochondria. Such cells are referred to as ρ or ρ petites. This study reports that minimal expression of human α-synuclein in yeast, from / promoter, gives rise to ρ petites. Interestingly, the full expression of α-synuclein, from the same promoters, in α-synuclein-triggered ρ petites and also in ρ petites (produced by treating ρ cells with the mutagen ethidium bromide) initiates apoptosis. The percentages of petites increase with increasing α-synuclein gene copy-number. ρ petites expressing α-synuclein from fully-induced / promoters exhibit increased ROS levels, loss of mitochondrial membrane potential, and nuclear DNA fragmentation, with increasing copies of α-synuclein. Our results indicate that, for the first time in yeast, α-synuclein-triggered apoptosis can occur independently of functional mitochondria. The observation that α-synuclein naturally forms petites and that they can undergo apoptosis may have important implications in understanding the pathogenesis of Parkinson's disease.