α-Synuclein toxicity in yeast and human cells is caused by cell cycle re-entry and autophagy degradation of ribonucleotide reductase 1

• Published in: Aging cell 2019-08, Vol.18 (4), p.1-15
• Main Authors: Marques, Maria Belém Sousa Sampaio, Guedes, Ana, Vasilevskiy, Igor, Gonçalves, Susana, Outeiro, Tiago F., Winderickx, Joris, Burhans, William C., Ludovico, Paula
• Format: Article
• Language: English
• Subjects: Aging; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; alpha-Synuclein - toxicity; Alpha‐synuclein; Analysis; Apoptosis; Autophagy; Autophagy - genetics; Biodegradation; Cell activation; Cell cycle; Cell cycle re‐entry; Cell death; Cell Death - genetics; Cell Line, Tumor; Cells; Cellular Senescence - genetics; Chronological aging; DNA damage; DNA Damage - genetics; DNA damage responses; DNA repair; Genetic Vectors; Glioma - pathology; Humans; Nervous system diseases; Neurodegenerative diseases; Original; Parkinson Disease - metabolism; Phagocytosis; Proteolysis; Reductase; Ribonuclease reductase; Ribonucleotide reductase; Ribonucleotide Reductases - metabolism; S Phase - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - metabolism; Science & Technology; Synuclein; Toxicity; Transfection
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.12922

α-Synuclein (aSyn) toxicity is associated with cell cycle alterations, activation of DNA damage responses (DDR), and deregulation of autophagy. However, the relationships between these phenomena remain largely unknown. Here, we demonstrate that in a yeast model of aSyn toxicity and aging, aSyn expression induces Ras2-dependent growth signaling, cell cycle re-entry, DDR activation, autophagy, and autophagic degradation of ribonucleotide reductase 1 (Rnr1), a protein required for the activity of ribonucleotide reductase and dNTP synthesis. These events lead to cell death and aging, which are abrogated by deleting RAS2, inhibiting DDR or autophagy, or overexpressing RNR1. aSyn expression in human H4 neuroglioma cells also induces cell cycle re-entry and S-phase arrest, autophagy, and degradation of RRM1, the human homologue of RNR1, and inhibiting autophagic degradation of RRM1 rescues cells from cell death. Our findings represent a model for aSyn toxicity that has important implications for understanding synucleinopathies and other age-related neurodegenerative diseases. Roswell Park Alliance Foundation, Roswell Park Cancer Institute; Fundação para a Ciência e Tecnologia (FCT, Portugal), Grant/ Award Number: SFRH/BPD/90533/2012; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB)