Replicative Reprogramming in the Context of Physiological Central Nervous System Aging and Age-related Neurodegeneration

In proliferation competent cells, irreversible cell cycle arrest is a key characteristic of cellular senescence. In mature post-mitotic neurons, however, where the paradigm of replicative senescence appears off target, the mechanisms of cellular aging are unclear. Recent evidence argues for the requirement of active cell cycle suppression in mature neurons, in order to prevent pseudo-replicative cellular events entailing genomic instability, neuronal dysfunction and cell cycle-related neuronal death. Therefore, we aimed at the characterization of a putative deregulated replicative program in CNS neurons and its importance for CNS aging and neurodegeneration. As model systems, CNS tissues from mice with an aged and progeroid phenotype, and a hSOD1^G93A-related murine model of fALS tagged with the cell cycle-sensitive Fucci (fluorescent ubiquitination-based cell-cycle indicator) reporter were used. Transcription-based and protein analyses comprising quantitative Wes techniques and systematic mass spectrometry evidenced broad alterations in phase-specific cell cycle regulators. Fucci reporter-based assignment of cell cycle phases linked to FACS-dependent DNA content analyses indicated altered molecular and genomic states favoring cell cycle progression under disease-like conditions. In support of this notion, ALS-severed motor neurons showed an elevated content of the G₁ phase regulator CyclinD1. Molecularly, we introduce the loss of the growth arrest-specific tumor suppressor Gas2 and its impact on the cell cycle-suppressive Cdk5-p35 complex as a putative inductive upstream cascade for cell cycle re-initiation, cytotoxic calpain hyperactivity and cell death. Decline of Gas2 eventuated early in the ALS-like pathogenesis, suggesting an inductive role for the disease manifestation. In summary, our data propose the process of replicative reprogramming as a putative counterpart of replicative senescence that might elucidate how mature neurons undergo aging, senescence and disease-related neurodegeneration.