New research shows that post-mitotic neurons in the brain, particularly in Alzheimer’s patients, can reenter the cell cycle and become senescent, providing potential insight into neurodegeneration and a new method of study brain diseases.
This rare process is more commonly seen in neurodegenerative diseases and could offer insight into disease mechanisms.
According to a new study published in Biology PLOS According to Kim Hai-Man Chow and colleagues at the Chinese University of Hong Kong, neurons in the brain that re-enter the cell cycle after mitosis are subject to rapid senescence, a process seen more frequently in Alzheimer’s disease. This discovery provides insight into neurodegeneration and suggests that the methods used can be applied to the study of other unique cell populations in the brain.
Most neurons in the brain are post-mitotic, meaning they have stopped dividing. For many years, it was assumed that this post-mitotic state was permanent. Recent findings have shown that a small proportion of neurons re-enter the cell cycle, but little is known about their fate after that.
Summary image of the article. The upper part highlights that neuronal cell cycle recommitment is a step of neuronal senescence and that their full molecular profiles can now be identified by the bioinformatics pipeline that we reported in the accepted manuscript. The bottom part is a simplified version of Figure 1A of the paper. The top panel is created by the BioRender application. Credit: Kim Hei-Man Chow (CC-BY 4.0)
To answer this question, the authors turned to publicly available databases of “snRNA-seq” data, in which individual nuclei are isolated and their RNA is sequenced, providing a snapshot of what a cell was doing at the time of isolation. The cell cycle goes through distinct phases, including growth, DNA synthesis, division-specific growth, and mitosis, and each phase is characterized by a specific set of proteins necessary for its completion. This allowed the authors to use all of the RNAs to tell them in which phase of the cycle a specific nucleus was located.
Their data included information on more than 30,000 nuclei, each of which was assigned a score based on the expression level of a set of about 350 cell cycle-related genes. They found that small populations of excitatory neurons were indeed reentered into the cell cycle. However, for the most part, these cells failed to continue through the cell cycle to produce daughter neurons. Instead, cells undergoing reentry also had elevated expression of senescence-associated genes; in fact, the cells had only awakened to enter senescence.
Implications for neurodegenerative diseases
Intriguingly, the authors found that neurons in the brains of Alzheimer’s patients reentered the cell cycle at a higher rate, and that neurons that were reentered the cell cycle and aged showed increased expression of several genes. associated with a higher risk of Alzheimer’s disease. including those that directly contribute to the production of amyloid, the sticky protein that aggregates in the AD brain. Similarly, the brains of patients with Parkinson’s disease and dementia with Lewy bodies had an increase in the proportion of reentrant neurons compared to healthy brains.
The neurobiological significance of this increased reentry for the diseased brain is not yet clear, but the analytical approach taken here could offer deeper insights into neuronal subpopulations in the brain, as well as shed light on the pathological mechanisms of diseases. neurodegenerative.
“Due to the rare existence and random localization of these cells in the brain, their molecular profiles and disease-specific heterogeneities remain unclear,” Chow said. “Although experimental validations of these results on relevant human samples will be conducted in the future, the applicability of this analytical approach to different diseases and crossesspecies These parameters provide new opportunities and perspectives to complement basic histological approaches in studying the roles of these cells in brain aging and disease pathogenesis.
The authors add: “This demonstrated bioinformatics analytical pipeline will offer the field a new tool to unbiasedly dissect cell cycle re-engaging and senescent neurons, and to dissect their heterogeneities in healthy and disease-affected brains.
The work was supported, in part, by grants from the following organizations: The Hong Kong Research Grants Council (RGC)-General Research Fund (GRF) (PI: ECS24107121, GRF16100219 and GRF16100718) (all to KH-MC) and the RGC- Collaborative Research Fund (CRF) (Co-I: C4033-19EF) (KH-MC); the National NaturalScience Foundation-Excellent Young Scientists Fund 2020 (Ref: 32022087) (KH-MC); Alzheimer’s Association Research Grant (PI: AARF-17-531566) (KH-MC).
