Cell Cycle Dynamics in Neurodegenerative Conditions

Neuronal development and maintenance rely on a permanent withdrawal from the cell cycle, ensuring stable connectivity and function. In neurodegenerative conditions, however, this quiescence is compromised by aberrant activation of cell cycle machinery in post-mitotic neurons. Such cell cycle re-entry may trigger DNA replication without mitosis, producing hyperploid cells that exhibit synaptic dysfunction, metabolic stress and, ultimately, apoptotic death. This phenomenon has been documented across Alzheimer’s disease, Parkinson’s disease and related disorders, where markers of G1, S and G2/M phases become detectable in vulnerable brain regions. Dysregulated cyclins, cyclin-dependent kinases and DNA-damage response proteins contribute to replication stress, genomic mosaicism and activation of pro-apoptotic programmes. Concurrently, altered activity of ubiquitin ligases and signalling pathways such as PI3K/Akt and ATM kinase further amplify neuronal vulnerability. Mechanistic insights into the balance between failed repair and chronic DNA damage have illuminated potential therapeutic strategies that aim to preserve neuronal quiescence or to modulate residual cell cycle proteins for neuroprotection. In sum, studying cell cycle dynamics in neurons offers a unified framework that links early synaptic impairment to late-stage cell death and provides routes to novel interventions for a range of neurodegenerative diseases.

Research from Nature Portfolio

Recent studies have demonstrated that forced cell cycle re-entry in mature cortical neurons leads to a cascade of dysfunctions reminiscent of early Alzheimer’s pathology. Experimental induction of S-phase markers produces widespread neuronal hyperploidy, accompanied by loss of axon initial segment integrity, reduction in dendritic synaptic puncta and diminished spontaneous firing. These hyperploid neurons survive longer when embedded in electrically active networks but show progressive synaptic failure and heightened susceptibility to delayed apoptosis. This work establishes a functional link between cell cycle reactivation, circuit integration and neuronal demise, underscoring the potential impact of aberrant replication cycles on cognitive decline and pointing to network activity as a modifier of neuron survival under pathological conditions.

Cell Cycle Dynamics in Neurodegenerative Conditions publication trend

The graph below shows the total number of articles in cell cycle dynamics in neurodegenerative conditions across all publications each year (not limited to Nature Index journals).

Technical terms

Cell cycle re-entry: Reactivation of DNA synthesis and mitotic regulatory processes in cells normally arrested in a non-dividing (G0) state, leading to replication stress if incomplete.

Hyperploidy: A condition in which cells contain excess chromosome sets or increased DNA content due to incomplete mitosis after DNA replication.

Post-mitotic neuron: A fully differentiated neuronal cell that has permanently exited the cell cycle and does not normally divide.

Cyclin-dependent kinases (CDKs): A family of serine/threonine kinases that, in complex with cyclins, orchestrate cell cycle phase transitions.

Apoptosis: Programmed cell death characterised by caspase activation, DNA fragmentation and cellular remodelling.

References

1. Role of RB1 in neurodegenerative diseases: inhibition of post-mitotic neuronal apoptosis via Kmt5b. Cell Death Discovery (2024).
2. Protein Kinase C-Delta Mediates Cell Cycle Reentry and Apoptosis Induced by Amyloid-Beta Peptide in Post-Mitotic Cortical Neurons. International Journal of Molecular Sciences (2024).
3. Cell cycle reentry triggers hyperploidization and synaptic dysfunction followed by delayed cell death in differentiated cortical neurons. Scientific Reports (2018).