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

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

doi:10.1111/acel.12922

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

Journal Article · Thu Apr 11 00:00:00 EDT 2019 · Aging Cell

DOI:https://doi.org/10.1111/acel.12922· OSTI ID:1506720

Sampaio‐Marques, Belém ^[1]; Guedes, Ana ^[1]; Vasilevskiy, Igor ^[1]; Gonçalves, Susana ^[2]; Outeiro, Tiago F. ^[3]; Winderickx, Joris ^[4]; Burhans, William C. ^[5];

^[1]

School of Medicine, Life and Health Sciences Research Institute (ICVS) University of Minho Braga Portugal, ICVS/3B’s ‐ PT Government Associate Laboratory Guimarães Portugal
Faculdade de Ciências Médicas, CEDOC – Chronic Diseases Research Center Universidade Nova de Lisboa Lisboa Portugal
Faculdade de Ciências Médicas, CEDOC – Chronic Diseases Research Center Universidade Nova de Lisboa Lisboa Portugal, Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) University Medical Center Göttingen Göttingen Germany, Center for Biostructural Imaging of Neurodegeneration Göttingen Germany, Max Planck Institute for Experimental Medicine Göttingen Germany
Functional Biology KU Leuven Heverlee Belgium
Department of Molecular and Cellular Biology Roswell Park Cancer Institute Buffalo New York

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.

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Sponsoring Organization:: USDOE

OSTI ID:: 1506720

Alternate ID(s):: OSTI ID: 1506721

Journal Information:: Aging Cell, Journal Name: Aging Cell Vol. 18 Journal Issue: 4; ISSN 1474-9718

Publisher:: Wiley-BlackwellCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 14 works

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