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

Belém Sampaio-Marques, Ana Guedes, Igor Vasilevskiy, Susana Gonçalves, Tiago F. Outeiro, Joris Winderickx, William C. Burhans, Paula Ludovico

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5 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Article numbere12922
JournalAging cell
Volume18
Issue number4
DOIs
Publication statusPublished - 1 Aug 2019

Keywords

  • alpha-synuclein
  • autophagy
  • cell cycle re-entry
  • chronological aging
  • DNA damage responses
  • ribonuclease reductase

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