Single-Nucleus Profiling Identifies Accelerated Oligodendrocyte Precursor Cell Senescence in a Mouse Model of Down Syndrome

Overview

Journal eNeuro

Specialty Neurology

Date 2023 Jul 25

PMID 37491366

Authors

Bianca Rusu

Bharti Kukreja

Taiyi Wu

Sophie J Dan

Min Yi Feng

Brian T Kalish

Affiliations

Soon will be listed here.

Abstract

Down syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive deficits. However, the mechanisms by which triplication of chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus ATAC and RNA-sequencing (snATAC-seq and snRNA-seq) analysis of the adult cortex. We identified cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discovered enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte (OL) precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We found that senescence is restricted to a subset of OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescued cortical OPC proliferation, restored microglial homeostasis, and improved contextual fear memory. Together, these findings suggest that cortical OPC senescence may be an important driver of neuropathology in DS.

References

Yeh H, Ikezu T . Transcriptional and Epigenetic Regulation of Microglia in Health and Disease. Trends Mol Med. 2018; 25(2):96-111. PMC: 6377292. DOI: 10.1016/j.molmed.2018.11.004. View

Mei L, Xiong W . Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat Rev Neurosci. 2008; 9(6):437-52. PMC: 2682371. DOI: 10.1038/nrn2392. View

Fan H, Zhao J, Yan J, Du G, Fu Q, Shi J . Effect of Notch1 gene on remyelination in multiple sclerosis in mouse models of acute demyelination. J Cell Biochem. 2018; 119(11):9284-9294. DOI: 10.1002/jcb.27197. View

Reeves R, Irving N, Moran T, WOHN A, Kitt C, Sisodia S . A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995; 11(2):177-84. DOI: 10.1038/ng1095-177. View

Puente-Bedia A, Berciano M, Martinez-Cue C, Lafarga M, Rueda N . Oxidative-Stress-Associated Proteostasis Disturbances and Increased DNA Damage in the Hippocampal Granule Cells of the Ts65Dn Model of Down Syndrome. Antioxidants (Basel). 2022; 11(12). PMC: 9774833. DOI: 10.3390/antiox11122438. View

Mei L, Nave K . Neuregulin-ERBB signaling in the nervous system and neuropsychiatric diseases. Neuron. 2014; 83(1):27-49. PMC: 4189115. DOI: 10.1016/j.neuron.2014.06.007. View

Xu R, Brawner A, Li S, Liu J, Kim H, Xue H . OLIG2 Drives Abnormal Neurodevelopmental Phenotypes in Human iPSC-Based Organoid and Chimeric Mouse Models of Down Syndrome. Cell Stem Cell. 2019; 24(6):908-926.e8. PMC: 6944064. DOI: 10.1016/j.stem.2019.04.014. View

Barlow G, Lyons G, Richardson J, Sarnat H, Korenberg J . DSCAM: an endogenous promoter drives expression in the developing CNS and neural crest. Biochem Biophys Res Commun. 2002; 299(1):1-6. DOI: 10.1016/s0006-291x(02)02548-2. View

Kong X, Worley L, Rinchai D, Bondet V, Jithesh P, Goulet M . Three Copies of Four Interferon Receptor Genes Underlie a Mild Type I Interferonopathy in Down Syndrome. J Clin Immunol. 2020; 40(6):807-819. PMC: 7418179. DOI: 10.1007/s10875-020-00803-9. View

10.

Escorihuela R, Fernandez-Teruel A, Vallina I, Baamonde C, Lumbreras M, Dierssen M . A behavioral assessment of Ts65Dn mice: a putative Down syndrome model. Neurosci Lett. 1995; 199(2):143-6. DOI: 10.1016/0304-3940(95)12052-6. View

11.

Kim M, Kim W, Kim D, Byun J, Huy H, Lee S . Macrophage migration inhibitory factor interacts with thioredoxin-interacting protein and induces NF-κB activity. Cell Signal. 2017; 34:110-120. DOI: 10.1016/j.cellsig.2017.03.007. View

12.

Coppe J, Desprez P, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. PMC: 4166495. DOI: 10.1146/annurev-pathol-121808-102144. View

13.

Chen H, Ho Y, Mezzadra R, Adrover J, Smolkin R, Zhu C . Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity. Cancer Discov. 2022; 13(2):432-453. PMC: 9901536. DOI: 10.1158/2159-8290.CD-22-0528. View

14.

Stuart T, Srivastava A, Madad S, Lareau C, Satija R . Single-cell chromatin state analysis with Signac. Nat Methods. 2021; 18(11):1333-1341. PMC: 9255697. DOI: 10.1038/s41592-021-01282-5. View

15.

Jin M, Xu R, Wang L, Alam M, Ma Z, Zhu S . Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer's disease. Cell Stem Cell. 2022; 29(7):1135-1153.e8. PMC: 9345168. DOI: 10.1016/j.stem.2022.06.007. View

16.

Salminen A, Kaarniranta K . Control of p53 and NF-κB signaling by WIP1 and MIF: role in cellular senescence and organismal aging. Cell Signal. 2010; 23(5):747-52. DOI: 10.1016/j.cellsig.2010.10.012. View

17.

Molagoda I, Jayasingha J, Choi Y, Jayasooriya R, Kang C, Kim G . Fisetin inhibits lipopolysaccharide-induced inflammatory response by activating β-catenin, leading to a decrease in endotoxic shock. Sci Rep. 2021; 11(1):8377. PMC: 8052411. DOI: 10.1038/s41598-021-87257-0. View

18.

Elsallabi O, Patruno A, Pesce M, Cataldi A, Carradori S, Gallorini M . Fisetin as a Senotherapeutic Agent: Biopharmaceutical Properties and Crosstalk between Cell Senescence and Neuroprotection. Molecules. 2022; 27(3). PMC: 8839434. DOI: 10.3390/molecules27030738. View

19.

Israel A . The IKK complex, a central regulator of NF-kappaB activation. Cold Spring Harb Perspect Biol. 2010; 2(3):a000158. PMC: 2829958. DOI: 10.1101/cshperspect.a000158. View

20.

Kobayashi H, Saragai S, Naito A, Ichio K, Kawauchi D, Murakami F . Calm1 signaling pathway is essential for the migration of mouse precerebellar neurons. Development. 2014; 142(2):375-84. DOI: 10.1242/dev.112680. View