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

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.

Comprehensive miRNome-Wide Profiling in a Neuronal Cell Model of Synucleinopathy Implies Involvement of Cell Cycle Genes

“…Due to its DNA-binding properties, a regulating role in transcription has been suggested ( Martins et al, 2011 ) which could result in the miRNA and gene expression alterations observed in our model. Furthermore, in accordance with our findings, an emerging body of evidence has linked PD and αSyn to cell cycle processes ( Lee et al, 2003 ; Höglinger et al, 2007 ; Ma et al, 2014 ; Paiva et al, 2017 ; Sampaio-Marques et al, 2019 ). An increased number of proteins associated with DNA synthesis and cell cycle re-entry was reported in dopaminergic neurons of postmortem PD brain tissue ( Höglinger et al, 2007 ).…”

“…Similar observations were made in cellular and animal models of PD ( Lee et al, 2003 ; Paiva et al, 2017 ). The atypical re-entry of post-mitotic dopaminergic neurons into the cell cycle is believed to cause apoptosis ( Sampaio-Marques et al, 2019 ), as well as nuclear accumulation of αSyn in PC12 cells ( Ma et al, 2014 ). Both of these effects were shown to promote neurotoxicity through cell cycle activation ( Ma et al, 2014 ).…”

“…As CCND1 expression in SNCA overexpressing human neurons over time was similar to SNCA levels and successful silencing of CCND1 reduced neuronal cell death, a correlation between aberrant cell cycle entry and αSyn-induced neurodegeneration might be well indicated in our model. The downstream effects of aberrant cell cycle activation in post-mitotic neurons resulting in cell death have already been established in multiple studies ( Freeman et al, 1994 ; Padmanabhan et al, 1999 ; Ino and Chiba, 2001 ; Jordan-Sciutto et al, 2003 ; Sumrejkanchanakij et al, 2003 ; Herrup and Yang, 2007 ; Höglinger et al, 2007 ; Pinho et al, 2019 ; Sampaio-Marques et al, 2019 ). Our findings suggest that miRNA dysregulation upon SNCA overexpression might be a very upstream activation mechanism for cell cycle re-activation in post-mitotic neurons.…”

Protective effect of <i>Vigna unguiculata</i> extract against aging and neurodegeneration

“…Several studies underline the relevant role of cellular models for a better understanding of the molecular regulation of human pathologies [15]. As such, budding yeast has been extensively employed in models of synucleinopathies [16][17][18][19]. In addition, an age-related degeneration of dopaminergic neurons has been shown in wild-type C. elegans [20].…”

Vitamin D, gut microbiota, and radiation-related resistance: a love-hate triangle

“…Moreover, is there a single core regulator of multiple radiation resistance-related signaling pathways, active during all radiation resistance processes? [23, 24].

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