LncRNA Is Upregulated in Aging Astrocytes and Regulates Neuronal Support Function Through Interaction with Npas3

Overview

Journal Noncoding RNA

Date 2025 Jan 23

PMID 39846680

Authors

Sophie Schroder

M Sadman Sakib

Dennis M Kruger

Tonatiuh Pena

Susanne Burkhardt

Anna-Lena Schutz

Farahnaz Sananbenesi

Andre Fischer

Affiliations

Soon will be listed here.

Abstract

Aging leads to cognitive decline and increased risk of neurodegenerative diseases. While molecular changes in central nervous system (CNS) cells contribute to this decline, the mechanisms are not fully understood. Long non-coding RNAs (lncRNAs) are key regulators of cellular functions. The roles of lncRNAs in aging, especially in glial cells, are not well characterized. We investigated lncRNA expression in non-neuronal cells from aged mice and identified 3222401L13Rik, a previously unstudied lncRNA, as upregulated in astrocytes during aging. Knockdown of 3222401L13Rik in primary astrocytes revealed its critical role in regulating genes for neuronal support and synapse organization, a function conserved in human iPSC-derived astrocytes. A 3222401L13Rik interacts with the transcription factor Neuronal PAS Domain Protein 3 (Npas3), and overexpression of Npas3 rescues deficits in astrocytes lacking 3222401L13Rik. These data suggest that 3222401L13Rik upregulation may help delay age-related cognitive decline.

References

Mattick J, Amaral P, Carninci P, Carpenter S, Chang H, Chen L . Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol. 2023; 24(6):430-447. PMC: 10213152. DOI: 10.1038/s41580-022-00566-8. View

Simchovitz A, Hanan M, Yayon N, Lee S, Bennett E, Greenberg D . A lncRNA survey finds increases in neuroprotective LINC-PINT in Parkinson's disease substantia nigra. Aging Cell. 2020; 19(3):e13115. PMC: 7059180. DOI: 10.1111/acel.13115. View

Lavedan C, Licamele L, Volpi S, Hamilton J, Heaton C, Mack K . Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study. Mol Psychiatry. 2008; 14(8):804-19. DOI: 10.1038/mp.2008.56. View

Brunskill E, Ehrman L, Williams M, Klanke J, Hammer D, Schaefer T . Abnormal neurodevelopment, neurosignaling and behaviour in Npas3-deficient mice. Eur J Neurosci. 2005; 22(6):1265-76. DOI: 10.1111/j.1460-9568.2005.04291.x. View

Royall D, Palmer R, Chiodo L, Polk M . Normal rates of cognitive change in successful aging: the freedom house study. J Int Neuropsychol Soc. 2006; 11(7):899-909. DOI: 10.1017/s135561770505109x. View

Damase T, Sukhovershin R, Boada C, Taraballi F, Pettigrew R, Cooke J . The Limitless Future of RNA Therapeutics. Front Bioeng Biotechnol. 2021; 9:628137. PMC: 8012680. DOI: 10.3389/fbioe.2021.628137. View

Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa R . Altered histone acetylation is associated with age-dependent memory impairment in mice. Science. 2010; 328(5979):753-6. DOI: 10.1126/science.1186088. View

Liau W, Samaddar S, Banerjee S, Bredy T . On the functional relevance of spatiotemporally-specific patterns of experience-dependent long noncoding RNA expression in the brain. RNA Biol. 2021; 18(7):1025-1036. PMC: 8216188. DOI: 10.1080/15476286.2020.1868165. View

Faghihi M, Modarresi F, Khalil A, Wood D, Sahagan B, Morgan T . Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase. Nat Med. 2008; 14(7):723-30. PMC: 2826895. DOI: 10.1038/nm1784. View

10.

Xu B, Zheng C . Analysis of Long Noncoding RNAs-Related Regulatory Mechanisms in Duchenne Muscular Dystrophy Using a Disease-Related lncRNA-mRNA Pathway Network. Genet Res (Camb). 2023; 2022:8548804. PMC: 9771664. DOI: 10.1155/2022/8548804. View

11.

Sun L, Cen Y, Liu X, Wei J, Ke X, Wang Y . Systemic whole transcriptome analysis identified underlying molecular characteristics and regulatory networks implicated in the retina following optic nerve injury. Exp Eye Res. 2024; 244:109929. DOI: 10.1016/j.exer.2024.109929. View

12.

Rodriguez J, Yeh C, Terzieva S, Olabarria M, Kulijewicz-Nawrot M, Verkhratsky A . Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol Aging. 2013; 35(1):15-23. DOI: 10.1016/j.neurobiolaging.2013.07.002. View

13.

Nassar A, Kodi T, Satarker S, Gurram P, Upadhya D, Sm F . Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions. Cells. 2022; 11(24). PMC: 9776935. DOI: 10.3390/cells11244111. View

14.

Fasolo F, Jin H, Winski G, Chernogubova E, Pauli J, Winter H . Long Noncoding RNA Controls Advanced Atherosclerotic Lesion Formation and Plaque Destabilization. Circulation. 2021; 144(19):1567-1583. PMC: 8570347. DOI: 10.1161/CIRCULATIONAHA.120.052023. View

15.

Li Y, Fan T, Li X, Liu L, Mao F, Li Y . Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors. Cell Rep. 2022; 40(9):111289. DOI: 10.1016/j.celrep.2022.111289. View

16.

Warner K, Hajdin C, Weeks K . Principles for targeting RNA with drug-like small molecules. Nat Rev Drug Discov. 2018; 17(8):547-558. PMC: 6420209. DOI: 10.1038/nrd.2018.93. View

17.

He B, Chen W, Zeng J, Tong W, Zheng P . Long noncoding RNA NKILA transferred by astrocyte-derived extracellular vesicles protects against neuronal injury by upregulating NLRX1 through binding to mir-195 in traumatic brain injury. Aging (Albany NY). 2021; 13(6):8127-8145. PMC: 8034961. DOI: 10.18632/aging.202618. View

18.

Wang F, Liang R, Soibam B, Yang J, Liu Y . Coregulatory long non-coding RNA and protein-coding genes in serum starved cells. Biochim Biophys Acta Gene Regul Mech. 2018; 1862(1):84-95. DOI: 10.1016/j.bbagrm.2018.11.004. View

19.

Kapranov P, Cheng J, Dike S, Nix D, Duttagupta R, Willingham A . RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 2007; 316(5830):1484-8. DOI: 10.1126/science.1138341. View

20.

Batiuk M, Martirosyan A, Wahis J, de Vin F, Marneffe C, Kusserow C . Identification of region-specific astrocyte subtypes at single cell resolution. Nat Commun. 2020; 11(1):1220. PMC: 7058027. DOI: 10.1038/s41467-019-14198-8. View