Aggregate Clearance of α-Synuclein in Saccharomyces cerevisiae Depends More on Autophagosome and Vacuole Function Than on the Proteasome

Petroi, Doris; Popova, Blagovesta; Taheri-Talesh, Naimeh; Irniger, Stefan; Shahpasandzadeh, Hedieh; Zweckstetter, Markus; Outeiro, Tiago F.; Braus, Gerhard H.

doi:10.1074/jbc.m112.361865

Cited by 69 publications

(111 citation statements)

References 73 publications

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“…8B). These results corroborate our previous findings (38). Western blot hybridization of MG132-treated cells with ubiquitin antibody confirmed the effectiveness of MG132 as a proteasome inhibitor (Fig.…”

Section: Phosphorylation Promotes Proteasome and Autophagy Degradatiosupporting

confidence: 93%

“…We previously showed that expression of WT ␣Syn from two copies is under the threshold for yeast growth inhibition (38). Thus, yeast smt3 ts strains expressing WT ␣Syn from two genomically integrated gene copies were constructed, and the number of integrated copies was verified by Southern hybridization.…”

Section: Resultsmentioning

confidence: 99%

“…All constructs were analyzed by sequencing. For microscopy analysis, all ␣Syn variants were tagged at the C terminus with GFP via the KLID linker (38).…”

Section: Methodsmentioning

confidence: 99%

“…Soluble ␣Syn can be targeted to the 26 S proteasome for degradation (31)(32)(33)(34) or can be degraded by the autophagy-lysosomal pathway (33)(34)(35)(36). The budding yeast Saccharomyces cerevisiae has been extensively used as a powerful system to study the basic molecular mechanisms involved in ␣Syn-mediated cytotoxicity (37)(38)(39)(40). We showed that aggregate clearance of ␣Syn depends mainly on the autophagy pathway (38).…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

“…The budding yeast Saccharomyces cerevisiae has been extensively used as a powerful system to study the basic molecular mechanisms involved in ␣Syn-mediated cytotoxicity (37)(38)(39)(40). We showed that aggregate clearance of ␣Syn depends mainly on the autophagy pathway (38). Here, we addressed the question of whether the crosstalk between specific post-translational modifications of ␣Syn modulates the processing of inclusions through degradation by autophagy or the proteasome.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

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Interplay between Sumoylation and Phosphorylation for Protection against α-Synuclein Inclusions

Shahpasandzadeh

Popova

Kleinknecht

et al. 2014

Journal of Biological Chemistry

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Background: Phosphorylation and sumoylation are post-translational modifications of the Parkinson disease protein ␣-synuclein. Results: ␣-Synuclein inclusion clearance is impaired in yeast when sumoylation is inhibited; phosphorylation of ␣-synuclein can compensate SUMO impairment. Conclusion: Sumoylation stimulates autophagy clearance of ␣-synuclein inclusions, whereas phosphorylation promotes autophagy and proteasome degradation. Significance: A complex molecular post-translational cross-talk is required in yeast to clear toxic inclusions.

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Section: Phosphorylation Promotes Proteasome and Autophagy Degradatiosupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

“…All constructs were analyzed by sequencing. For microscopy analysis, all ␣Syn variants were tagged at the C terminus with GFP via the KLID linker (38).…”

Section: Methodsmentioning

confidence: 99%

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

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Interplay between Sumoylation and Phosphorylation for Protection against α-Synuclein Inclusions

Shahpasandzadeh

Popova

Kleinknecht

et al. 2014

Journal of Biological Chemistry

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Behead and live long or the tale of cathepsin L

Streubel

Bischof

Weiss

et al. 2017

Yeast

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In recent decades Saccharomyces cerevisiae has proven to be one of the most valuable model organisms of aging research. Pathways such as autophagy or the effect of substances like resveratrol and spermidine that prolong the replicative as well as chronological lifespan of cells were described for the first time in S. cerevisiae. In this study we describe the establishment of an aging reporter that allows a reliable and relative quick screening of substances and genes that have an impact on the replicative lifespan. A cDNA library of the flatworm Dugesia tigrina that can be immortalized by beheading was screened using this aging reporter. Of all the flatworm genes, only one could be identified that significantly increased the replicative lifespan of S.cerevisiae. This gene is the cysteine protease cathepsin L that was sequenced for the first time in this study. We were able to show that this protease has the capability to degrade such proteins as the yeast Sup35 protein or the human α-synuclein protein in yeast cells that are both capable of forming cytosolic toxic aggregates. The degradation of these proteins by cathepsin L prevents the formation of these unfolded protein aggregates and this seems to be responsible for the increase in replicative lifespan.

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