Abstract DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase, and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson’s disease remains elusive. Here, using a comparative proteomic analysis between wild-type cortical neurons and neurons lacking DJ-1 (data available via ProteomeXchange, identifier PXD029351), we show that this protein is involved in cell cycle checkpoints disruption. We detect increased amount of p-tau and α-synuclein proteins, altered phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) signalling pathways, and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation, and the establishment of synapses, but can also contribute to cell cycle progression in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1-associated PD. Therefore, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies. Graphical Abstract