Neuronal cell cycle reentry events in the aging brain are more prevalent in neurodegeneration and lead to cellular senescence

Abstract

Increasing evidence indicates that terminally differentiated neurons in the brain may recommit to a cell cycle-like process during neuronal aging and under disease conditions. Because of the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear. Through a bioinformatics approach that allows integrated analyses of multiple single-nucleus transcriptome datasets from human brain samples, these rare cell populations were identified and selected for further characterization. Our analyses indicated that these cell cycle-related events occur predominantly in excitatory neurons and that cellular senescence is likely their immediate terminal fate. Quantitatively, the number of cell cycle re-engaging and senescent neurons decreased during the normal brain aging process, but in the context of late-onset Alzheimer’s disease (AD), these cells accumulate instead. Transcriptomic profiling of these cells suggested that disease-specific differences were predominantly tied to the early stage of the senescence process, revealing that these cells presented more proinflammatory, metabolically deregulated, and pathology-associated signatures in disease-affected brains. Similarly, these general features of cell cycle re-engaging neurons were also observed in a subpopulation of dopaminergic neurons identified in the Parkinson’s disease (PD)-Lewy body dementia (LBD) model. An extended analysis conducted in a mouse model of brain aging further validated the ability of this bioinformatics approach to determine the robust relationship between the cell cycle and senescence processes in neurons in this cross-species setting.

Parkinson’s disease-associated shifts between DNA methylation and DNA hydroxymethylation in human brain

“…We also identified genes involved in cell cycle and senescence pathways (1,12), consistent with evidence that neuronal cell cycle reentry events and cellular senescence in the aging brain can lead to degeneration. 93–95 Finally, we observed epigenetic regulation of multiple epigenetic regulators themselves (6).…”

“…We also identified genes involved in cell cycle and senescence pathways (1,12), consistent with evidence that neuronal cell cycle reentry events and cellular senescence in the aging brain can lead to degeneration. [93][94][95] Finally, we observed epigenetic regulation of multiple epigenetic regulators themselves (6). While these changes were not assessed in the SN, the region most commonly studied in the context of PD, by using the parietal cortex, which does not have widespread degeneration, we were able to assess neuron-specific DNA modifications associated with PD in a region without widespread neuron loss prior to the onset of pathology within the parietal cortex.…”