DNA Damage Response-Associated Cell Cycle Re-Entry and Neuronal Senescence in Brain Aging and Alzheimer's Disease

Overview

Journal J Alzheimers Dis

Publisher Sage Publications

Specialties Geriatrics
Neurology

Date 2022 Jul 18

PMID 35848025

Authors

Genper Chi-Ngai Wong

Kim Hei-Man Chow

Affiliations

Soon will be listed here.

Abstract

Chronological aging is by far the strongest risk factor for age-related dementia and Alzheimer's disease. Senescent cells accumulated in the aging and Alzheimer's disease brains are now recognized as the keys to describing such an association. Cellular senescence is a classic phenomenon characterized by stable cell arrest, which is thought to be applicable only to dividing cells. Emerging evidence indicates that fully differentiated post-mitotic neurons are also capable of becoming senescent, with roles in contributing to both brain aging and disease pathogenesis. The key question that arises is the identity of the upstream triggers and the molecular mechanisms that underly such changes. Here, we highlight the potential role of persistent DNA damage response as the major driver of senescent phenotypes and discuss the current evidence and molecular mechanisms that connect DNA repair infidelity, cell cycle re-entry and terminal fate decision in committing neuronal cell senescence.

Citing Articles

Multi-modal investigation reveals pathogenic features of diverse DDX3X missense mutations.

Mosti F, Hoye M, Escobar-Tomlienovich C, Silver D PLoS Genet. 2025; 21(1):e1011555.

PMID: 39836689 PMC: 11771946. DOI: 10.1371/journal.pgen.1011555.

Ezh2 Delays Activation of Differentiation Genes During Normal Cerebellar Granule Neuron Development and in Medulloblastoma.

Purzner J, Brown A, Purzner T, Ellis L, Broski S, Litzenburger U bioRxiv. 2024; .

PMID: 39605517 PMC: 11601632. DOI: 10.1101/2024.11.21.624171.

Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration.

Terao R, Sohn B, Yamamoto T, Lee T, Colasanti J, Pfeifer C Invest Ophthalmol Vis Sci. 2024; 65(10):29.

PMID: 39167399 PMC: 11343002. DOI: 10.1167/iovs.65.10.29.

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

Wu D, Sun J, Chow K PLoS Biol. 2024; 22(4):e3002559.

PMID: 38652714 PMC: 11037540. DOI: 10.1371/journal.pbio.3002559.

Extracellular vesicles from human urine-derived stem cells delay aging through the transfer of PLAU and TIMP1.

Rao S, He Z, Wang Z, Yin H, Hu X, Tan Y Acta Pharm Sin B. 2024; 14(3):1166-1186.

PMID: 38487008 PMC: 10935484. DOI: 10.1016/j.apsb.2023.12.009.

References

Krenning L, Feringa F, Shaltiel I, van den Berg J, Medema R . Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell. 2014; 55(1):59-72. DOI: 10.1016/j.molcel.2014.05.007. View

Shen X, Chen J, Li J, Kofler J, Herrup K . Neurons in Vulnerable Regions of the Alzheimer's Disease Brain Display Reduced ATM Signaling. eNeuro. 2016; 3(1). PMC: 4770009. DOI: 10.1523/ENEURO.0124-15.2016. View

Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A . Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell. 2012; 11(6):996-1004. PMC: 3533793. DOI: 10.1111/j.1474-9726.2012.00870.x. View

Palmer A, Gustafson B, Kirkland J, Smith U . Cellular senescence: at the nexus between ageing and diabetes. Diabetologia. 2019; 62(10):1835-1841. PMC: 6731336. DOI: 10.1007/s00125-019-4934-x. View

Weissman L, Jo D, Sorensen M, de Souza-Pinto N, Markesbery W, Mattson M . Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment. Nucleic Acids Res. 2007; 35(16):5545-55. PMC: 2018628. DOI: 10.1093/nar/gkm605. View

Effros R . Kleemeier Award Lecture 2008--the canary in the coal mine: telomeres and human healthspan. J Gerontol A Biol Sci Med Sci. 2009; 64(5):511-5. PMC: 2800806. DOI: 10.1093/gerona/glp001. View

Mondello C, Petropoulou C, Monti D, Gonos E, Franceschi C, Nuzzo F . Telomere length in fibroblasts and blood cells from healthy centenarians. Exp Cell Res. 1999; 248(1):234-42. DOI: 10.1006/excr.1999.4398. View

Yoon Y, You J, Kim T, Ahn W, Kim M, Son K . Senescence and impaired DNA damage responses in alpha-synucleinopathy models. Exp Mol Med. 2022; 54(2):115-128. PMC: 8894476. DOI: 10.1038/s12276-022-00727-x. View

Riessland M, Kolisnyk B, Kim T, Cheng J, Ni J, Pearson J . Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons. Cell Stem Cell. 2019; 25(4):514-530.e8. PMC: 7493192. DOI: 10.1016/j.stem.2019.08.013. View

10.

Chow H, Shi M, Cheng A, Gao Y, Chen G, Song X . Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence. Nat Neurosci. 2019; 22(11):1806-1819. DOI: 10.1038/s41593-019-0505-1. View

11.

Takai H, Smogorzewska A, de Lange T . DNA damage foci at dysfunctional telomeres. Curr Biol. 2003; 13(17):1549-56. DOI: 10.1016/s0960-9822(03)00542-6. View

12.

Serra V, von Zglinicki T . Human fibroblasts in vitro senesce with a donor-specific telomere length. FEBS Lett. 2002; 516(1-3):71-4. DOI: 10.1016/s0014-5793(02)02504-8. View

13.

Barreto G, Schafer A, Marhold J, Stach D, Swaminathan S, Handa V . Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature. 2007; 445(7128):671-5. DOI: 10.1038/nature05515. View

14.

Bae T, Tomasini L, Mariani J, Zhou B, Roychowdhury T, Franjic D . Different mutational rates and mechanisms in human cells at pregastrulation and neurogenesis. Science. 2017; 359(6375):550-555. PMC: 6311130. DOI: 10.1126/science.aan8690. View

15.

Haince J, Kozlov S, Dawson V, Dawson T, Hendzel M, Lavin M . Ataxia telangiectasia mutated (ATM) signaling network is modulated by a novel poly(ADP-ribose)-dependent pathway in the early response to DNA-damaging agents. J Biol Chem. 2007; 282(22):16441-53. DOI: 10.1074/jbc.M608406200. View

16.

Gupta S, You P, SenGupta T, Nilsen H, Sharma K . Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases. Biology (Basel). 2021; 10(2). PMC: 7922961. DOI: 10.3390/biology10020163. View

17.

Iyama T, Wilson 3rd D . DNA repair mechanisms in dividing and non-dividing cells. DNA Repair (Amst). 2013; 12(8):620-36. PMC: 3720834. DOI: 10.1016/j.dnarep.2013.04.015. View

18.

Magrassi L, Leto K, Rossi F . Lifespan of neurons is uncoupled from organismal lifespan. Proc Natl Acad Sci U S A. 2013; 110(11):4374-9. PMC: 3600460. DOI: 10.1073/pnas.1217505110. View

19.

Welty S, Teng Y, Liang Z, Zhao W, Sanders L, Greenamyre J . RAD52 is required for RNA-templated recombination repair in post-mitotic neurons. J Biol Chem. 2017; 293(4):1353-1362. PMC: 5787811. DOI: 10.1074/jbc.M117.808402. View

20.

Herrup K, Neve R, Ackerman S, Copani A . Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci. 2004; 24(42):9232-9. PMC: 6730083. DOI: 10.1523/JNEUROSCI.3347-04.2004. View