Yeasts as Complementary Model Systems for the Study of the Pathological Repercussions of Enhanced Synphilin-1 Glycation and Oxidation

• Published in: International journal of molecular sciences 2021-02, Vol.22 (4), p.1677
• Main Authors: Seynnaeve, David, Mulvihill, Daniel P, Winderickx, Joris, Franssens, Vanessa
• Format: Article
• Language: English
• Subjects: Age; Alcohol Oxidoreductases - genetics; Alcohol Oxidoreductases - metabolism; Aldehyde reductase; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - genetics; Aldehyde Reductase - metabolism; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Deregulation; Fluorescence; Genes; Glucose; Glycerol; Glycosylation; Humans; Inclusion Bodies; Inclusions; Lactoylglutathione Lyase - antagonists & inhibitors; Lactoylglutathione Lyase - genetics; Lactoylglutathione Lyase - metabolism; Lewy bodies; Metabolism; Mitochondrial DNA; Nerve Tissue Proteins - chemistry; Nerve Tissue Proteins - metabolism; Oxidation; Oxidation-Reduction; Oxidative Stress; Parkinson's disease; Proteins; Reductases; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Schizosaccharomyces pombe; Synuclein; Yeast
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22041677

Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were investigated. To this end, either fluorescent dsRed-tagged or non-tagged human , which encodes the Synphilin-1 protein, was expressed in and yeast strains devoid of enzymes Glo1, Glo2, and Gre3. Presented data shows that lack of Glo2 and Gre3 activity in increases the formation of large Synphilin-1 inclusions. This correlates with enhanced oxidative stress levels and an inhibitory effect on exponential growth, which is most likely caused by deregulation of autophagic degradation capacity, due to excessive Synphilin-1 aggresome build-up. These findings illustrate the detrimental impact of increased oxidation and glycation on Synphilin-1 inclusion formation. Similarly, polar-localised inclusions were observed in wild-type cells and strains deleted for either or . Contrary to , however, no growth defects were observed upon expression of . Altogether, our findings show the relevance of yeasts, especially , as complementary models to unravel mechanisms contributing to Synphilin-1 pathology in the context of neurodegenerative diseases.