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

ABSTRACT: Human ?-synuclein expression in baker's yeast reportedly induces mitochondria-dependent apoptosis. Surprisingly, we find that, under de-repressing conditions of the inducible MET25/GAL1 promoters, yeast cells expressing chromosomally-integrated copies of the human ?-synuclein gene are not killed, but spontaneously form respiration-deficient rho-minus (?-) 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 ?0 or ?- petites. This study reports that minimal expression of human ?-synuclein in yeast, from MET25/GAL1 promoter, gives rise to ?- petites. Interestingly, the full expression of ?-synuclein, from the same promoters, in ?-synuclein-triggered ?- petites and also in ?0 petites (produced by treating ?+ cells with the mutagen ethidium bromide) initiates apoptosis. The percentages of petites increase with increasing ?-synuclein gene copy-number. ?- petites expressing ?-synuclein from fully-induced MET25/GAL1 promoters exhibit increased ROS levels, loss of mitochondrial membrane potential, and nuclear DNA fragmentation, with increasing copies of ?-synuclein. Our results indicate that, for the first time in yeast, ?-synuclein-triggered apoptosis can occur independently of functional mitochondria. The observation that ?-synuclein naturally forms petites and that they can undergo apoptosis may have important implications in understanding the pathogenesis of Parkinson's disease.

SUBMITTER: Akintade DD

PROVIDER: S-EPMC7601298 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Akintade Damilare D DD Chaudhuri Bhabatosh B

Cells 20200929 10

Human α-synuclein expression in baker's yeast reportedly induces mitochondria-dependent apoptosis. Surprisingly, we find that, under de-repressing conditions of the inducible <i>MET25/GAL1</i> promoters, yeast cells expressing chromosomally-integrated copies of the human α-synuclein gene are not killed, but spontaneously form respiration-deficient rho-minus (ρ<sup>-</sup>) petites. Although yeast cells can undergo cell death (apoptosis) from loss of mitochondrial function, they can also survive ...[more]

PMID: 33003464

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Project description:Methamphetamine (METH) is an illegal and widely abused psychoactive stimulant. METH abusers are at high risk of neurodegenerative disorders, including Parkinson's disease (PD). Previous studies have demonstrated that METH causes alpha-synuclein (?-syn) aggregation in the both laboratory animal and human. In this study, exposure to high METH doses increased the expression of ?-syn and the small ubiquitin-related modifier 1 (SUMO-1). Therefore, we hypothesized that SUMOylation of ?-syn is involved in high-dose METH-induced ?-syn aggregation. We measured the levels of ?-syn SUMOylation and these enzymes involved in the SUMOylation cycle in SH-SY5Y human neuroblastoma cells (SH-SY5Y cells), in cultures of C57 BL/6 primary mouse neurons and in brain tissues of mice exposure to METH. We also demonstrated the effect of ?-syn SUMOylation on ?-syn aggregation after METH exposure by overexpressing the key enzyme of the SUMOylation cycle or silencing SUMO-1 expression in vitro. Then, we make introduced mutations in the major SUMOylation acceptor sites of ?-syn by transfecting a lentivirus containing the sequence of WT ?-syn or K96/102R ?-syn into SH-SY5Y cells and injecting an adenovirus containing the sequence of WT ?-syn or K96/102R ?-syn into the mouse striatum. Levels of the ubiquitin-proteasome system (UPS)-related makers ubiquitin (Ub) and UbE1, as well as the autophagy-lysosome pathway (ALP)-related markers LC3, P62 and lysosomal associated membrane protein 2A (LAMP2A), were also measured in SH-SY5Y cells transfected with lentivirus and mice injected with adenovirus. The results showed that METH exposure decreases the SUMOylation level of ?-syn, although the expression of ?-syn and SUMO-1 are increased. One possible cause is the reduction of UBC9 level. The increase in ?-syn SUMOylation by UBC9 overexpression relieves METH-induced ?-syn overexpression and aggregation, whereas the decrease in ?-syn SUMOylation by SUMO-1 silencing exacerbates the same pathology. Furthermore, mutations in the major SUMOylation acceptor sites of ?-syn also aggravate ?-syn overexpression and aggregation by impairing degradation through the UPS and the ALP in vitro and in vivo. These results suggest that SUMOylation of ?-syn plays a fundamental part in ?-syn overexpression and aggregation induced by METH and could be a suitable target for the treatment of neurodegenerative diseases.

Dataset Information

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

Publications

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

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