Cell Cycle Re-entry in the Nervous System: From Polyploidy to Neurodegeneration

Abstract

Terminally differentiated cells of the nervous system have long been considered to be in a stable non-cycling state and are often considered to be permanently in G0. Exit from the cell cycle during development is often coincident with the differentiation of neurons, and is critical for neuronal function. But what happens in long lived postmitotic tissues that accumulate cell damage or suffer cell loss during aging? In other contexts, cells that are normally non-dividing or postmitotic can or re-enter the cell cycle and begin replicating their DNA to facilitate cellular growth in response to cell loss. This leads to a state called polyploidy, where cells contain multiple copies of the genome. A growing body of literature from several vertebrate and invertebrate model organisms has shown that polyploidy in the nervous system may be more common than previously appreciated and occurs under normal physiological conditions. Moreover, it has been found that neuronal polyploidization can play a protective role when cells are challenged with DNA damage or oxidative stress. By contrast, work over the last two and a half decades has discovered a link between cell-cycle reentry in neurons and several neurodegenerative conditions. In this context, neuronal cell cycle re-entry is widely considered to be aberrant and deleterious to neuronal health. In this review, we highlight historical and emerging reports of polyploidy in the nervous systems of various vertebrate and invertebrate organisms. We discuss the potential functions of polyploidization in the nervous system, particularly in the context of long-lived cells and age-associated polyploidization. Finally, we attempt to reconcile the seemingly disparate associations of neuronal polyploidy with both neurodegeneration and neuroprotection.

Deficiency of Parkinson’s Related Protein DJ-1 Alters Cdk5 Signalling and Induces Neuronal Death by Aberrant Cell Cycle Re-entry

“…5F). This indicates an enlargement of the S and G2/M phases in dj1 −/− cortical neurons, as previously described for mouse embryonic fibroblasts deficient in DJ-1 (Requejo-Aguilar et al 2015), that has been linked to neurodegeneration (Sharma et al 2017;Frade and Ovejero-Benito 2015;Nandakumar et al 2021).…”

Model scenarios for cell cycle re-entry in Alzheimer's disease

“…The activation of E2F is irreversible with respect to DNA damage ( Figure 8 C) due to the feedback loop regulation involving Rb and E2F (Rb --| E2F → CycE-Cdk2 --| Rb). This suggests that once neurons commit to cell cycle re-entry, then there is no point-of-return and may undergo polyploidization ( Nandakumar et al., 2021 ). p53 killer activation shows bistable activation at a higher level of DNA damage ( Figure 8 D).…”

Polyploidy as a Fundamental Phenomenon in Evolution, Development, Adaptation and Diseases

“…In human and warm-blooded animals, polyploidy can be a part of normal postnatal morphogenetic programs and can be a manifestation of response to pathological stimuli and diseases. Thus, polyploid cells arise in normal organogenesis of heart, neuronal glia, cerebellum, neocortex, retina, liver, placenta, blood vessels, skin, blood, and other organs [ 3 , 22 , 71 , 72 , 73 , 74 ] and in atherosclerosis, neurodegenerative disorders, cardiovascular diseases, wound healing, inflammation, diabetes, cancer, and other pathologies [ 1 , 7 , 8 , 72 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Despite the prevalence in normal physiology and pathology, the functional significance of polyploidy still is not clear.…”

“…The association between polyploidy, adaptation to stress, carcinogenesis, and decrease in organ functional potential suggests that genome accumulation is involved in the regulation of gene expression. The analysis of gene expression in the human and mouse hepatocytes, cardiomyocytes, trophoblast cells, neurons, adipose mesenchymal stem cells, interstitial cardiac stem cells, drosophila epithelial cells, and various types of cancer cells indicate that polyploidy can exert both common and specific effects [ 7 , 69 , 73 , 78 , 83 , 84 , 110 , 111 , 112 ]. The common effects are the induction of biological pathways related to stress response (i.e., abiotic, biotic, hypoxic, oxidative, genotoxic, and inflammatory), response to DNA instability, and drug resistance [ 7 , 57 , 69 , 72 , 83 , 87 , 113 , 114 , 115 ].…”