Skip to main content
SpringerLink
Log in

Aging-accelerated differential production and aggregation of STAT3 protein in neuronal cells and neural stem cells in the male mouse spinal cord

  • Research Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

Aging-affected cellular compositions of the spinal cord are diverse and region specific. Age leads to the accumulation of abnormal protein aggregates and dysregulation of proteostasis. Dysregulated proteostasis and protein aggregates result from dysfunction of the ubiquitin-proteasome system (UPS) and autophagy. Understanding the molecular mechanisms of spinal cord aging is essential and important for scientists to discover new therapies for rejuvenation. We found age-related increases in STAT3 and decreases in Tuj1 in aging mouse spinal cords, which was characterized by increased expression of P16. Coaggregation of lysine-48 and lysine-63 ubiquitin with STAT3 was revealed in aging mouse spinal cords. STAT3-ubiquitin aggregates formed via lysine-48 and lysine-63 linkages were increased significantly in the aging spinal cords but not in central canal ependymal cells or neural stem cells in the spinal cord. These results highlight the increase in STAT3 and its region-specific aggregation and ubiquitin-conjugation during spinal cord aging.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Abubakar MB, Sanusi KO et al (2022) Alzheimer’s disease: an update and insights into pathophysiology. Front Aging Neurosci 14:742408

    Article  CAS  Google Scholar 

  • Audesse AJ, Dhakal S et al (2019) FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells. PLoS Genet 15(4):e1008097

    Article  CAS  Google Scholar 

  • Bhat KP, Yan S et al (2014) Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A. Proc Natl Acad Sci USA 111(15):5706–5711

    Article  CAS  Google Scholar 

  • Bilkei-Gorzo A, Albayram O et al (2017) A chronic low dose of Delta(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med 23(6):782–787

    Article  CAS  Google Scholar 

  • Brunet A, Goodell MA et al (2022) Ageing and rejuvenation of tissue stem cells and their niches. Nat Rev Mol Cell Biol. https://doi.org/10.1038/s41580-022-00510-w

    Article  Google Scholar 

  • Chazaud B, Mouchiroud G (2014) Inflamm-aging: STAT3 signaling pushes muscle stem cells off balance. Cell Stem Cell 15(4):401–402

    Article  CAS  Google Scholar 

  • Chevreau R, Ghazale H et al (2021) RNA profiling of mouse ependymal cells after spinal cord injury identifies the oncostatin pathway as a potential key regulator of spinal cord stem cell fate. Cells 10(12):3332

    Article  CAS  Google Scholar 

  • Chondrogianni N, Georgila K et al (2015) 20S proteasome activation promotes life span extension and resistance to proteotoxicity in Caenorhabditis elegans. FASEB J 29(2):611–622

    Article  CAS  Google Scholar 

  • De Butte-Smith M, Zukin RS et al (2012) Effects of global ischemia and estradiol pretreatment on phosphorylation of Akt, CREB and STAT3 in hippocampal CA1 of young and middle-aged female rats. Brain Res 1471:118–128

    Article  Google Scholar 

  • Dikic I, Dotsch V (2009) Ubiquitin linkages make a difference. Nat Struct Mol Biol 16(12):1208–1210

    Article  Google Scholar 

  • Fu Y, Yu Y et al (2015) Aging-dependent changes in the cellular composition of the mouse brain and spinal cord. Neuroscience 290:406–420

    Article  CAS  Google Scholar 

  • Gilchrist CA, Gray DA et al (2005) Effect of ubiquitin expression on neuropathogenesis in a mouse model of familial amyotrophic lateral sclerosis. Neuropathol Appl Neurobiol 31(1):20–33

    Article  CAS  Google Scholar 

  • Gleixner AM, Pulugulla SH et al (2014) Impact of aging on heat shock protein expression in the substantia nigra and striatum of the female rat. Cell Tissue Res 357(1):43–54

    Article  CAS  Google Scholar 

  • Grice GL, Nathan JA (2016) The recognition of ubiquitinated proteins by the proteasome. Cell Mol Life Sci 73(18):3497–3506

    Article  CAS  Google Scholar 

  • Grillari J, Katinger H et al (2006) Aging and the ubiquitinome: traditional and non-traditional functions of ubiquitin in aging cells and tissues. Exp Gerontol 41(11):1067–1079

    Article  CAS  Google Scholar 

  • Ijaz S, Mohammed I et al (2020) Modulating pro-inflammatory cytokines, tissue damage magnitude, and motor deficit in spinal cord injury with subventricular zone-derived extracellular vesicles. J Mol Neurosci 70(3):458–466

    Article  CAS  Google Scholar 

  • Jacobson AD, Zhang NY et al (2009) The Lysine 48 and Lysine 63 ubiquitin conjugates are processed differently by the 26 S proteasome. J Biol Chem 284(51):35485–35494

    Article  CAS  Google Scholar 

  • Kamiya K, Furuya T et al (2017) Exploration of spinal cord aging-related proteins using a proteomics approach. J Exp Neurosci 11:1179069517713019

    Article  Google Scholar 

  • Keller JN, Huang FF et al (2000) Decreased levels of proteasome activity and proteasome expression in aging spinal cord. Neuroscience 98(1):149–156

    Article  CAS  Google Scholar 

  • Kevei E, Hoppe T (2014) Ubiquitin sets the timer: impacts on aging and longevity. Nat Struct Mol Biol 21(4):290–292

    Article  CAS  Google Scholar 

  • Khatiwala RV, Zhang SN et al (2018) Inhibition of p16(INK4A) to rejuvenate aging human cardiac progenitor cells via the upregulation of anti-oxidant and NF kappa B signal pathways. Stem Cell Rev Rep 14(4):612–625

    Article  CAS  Google Scholar 

  • Kobayashi T, Piao W et al (2019) Enhanced lysosomal degradation maintains the quiescent state of neural stem cells. Nat Commun 10(1):5446

    Article  Google Scholar 

  • Krishnan VS, Shavlakadze T et al (2018) Age-related loss of VGLUT1 excitatory, but not VGAT inhibitory, immunoreactive terminals on motor neurons in spinal cords of old sarcopenic male mice. Biogerontology 19(5):385–399

    Article  CAS  Google Scholar 

  • Lanke V, Moolamalla STR et al (2018) Integrative analysis of hippocampus gene expression profiles identifies network alterations in aging and Alzheimer’s disease. Front Aging Neurosci 10:153

    Article  Google Scholar 

  • Leeman DS, Hebestreit K et al (2018) Lysosome activation clears aggregates and enhances quiescent neural stem cell activation during aging. Science 359(6381):1277–1283

    Article  CAS  Google Scholar 

  • Li PL, Huang ZM et al (2019) Ubiquitin-specific peptidase 28 enhances STAT3 signaling and promotes cell growth in non-small-cell lung cancer. Onco Targets Ther 12:1603–1611

    Article  CAS  Google Scholar 

  • Li X, Yang KB et al (2021) CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. Autophagy 17(12):4323–4340

    Article  CAS  Google Scholar 

  • Lim KL, Dawson VL et al (2006) Parkin-mediated lysine 63-linked polyubiquitination: a link to protein inclusions formation in Parkinson’s and other conformational diseases? Neurobiol Aging 27(4):524–529

    Article  CAS  Google Scholar 

  • Liu C, Fei EK et al (2007) Assembly of lysine 63-linked ubiquitin conjugates by phosphorylated alpha-synuclein implies Lewy body biogenesis. J Biol Chem 282(19):14558–14566

    Article  CAS  Google Scholar 

  • Liu C, Zhang DJ et al (2015) DPF2 regulates OCT4 protein level and nuclear distribution. Biochim Biophys Acta Mol Cell Res 1853(12):3279–3293

    Article  CAS  Google Scholar 

  • Liu C, Sun RY et al (2017) The BAF45D protein is preferentially expressed in adult neurogenic zones and in neurons and may be required for retinoid acid induced PAX6 expression. Front Neuroanat 11:94

    Article  Google Scholar 

  • Liu XY, Mao Y et al (2020) MicroRNA-127 promotes anti-microbial host defense through restricting A20-mediated de-ubiquitination of STAT3. iScience 23(1):100763

    Article  CAS  Google Scholar 

  • Madeo F, Zimmermann A et al (2015) Essential role for autophagy in life span extension. J Clin Invest 125(1):85–93

    Article  Google Scholar 

  • Mallette FA, Richard S (2012) K48-linked ubiquitination and protein degradation regulate 53BP1 recruitment at DNA damage sites. Cell Res 22(8):1221–1223

    Article  CAS  Google Scholar 

  • Mohammed S, Nicklas EH et al (2021) Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress. Free Radic Biol Med 164:315–328

    Article  CAS  Google Scholar 

  • Myeku N, Wang H et al (2012) cAMP stimulates the ubiquitin/proteasome pathway in rat spinal cord neurons. Neurosci Lett 527(2):126–131

    Article  CAS  Google Scholar 

  • Negredo PN, Yeo RW et al (2020) Aging and rejuvenation of neural stem cells and their niches. Cell Stem Cell 27(2):202–223

    Article  Google Scholar 

  • Noor NM, Mollgard K et al (2013) Expression and cellular distribution of ubiquitin in response to injury in the developing spinal cord of Monodelphis domestica. PLoS ONE. https://doi.org/10.1371/journal.pone.0062120

    Article  Google Scholar 

  • Pareja-Cajiao M, Gransee HM et al (2021) Age-related impairment of autophagy in cervical motor neurons. Exp Gerontol 144:111193

    Article  CAS  Google Scholar 

  • Park CW, Jung BK et al (2020) Reduced free ubiquitin levels and proteasome activity in cultured neurons and brain tissues treated with amyloid beta aggregates. Mol Brain 13(1):89

    Article  CAS  Google Scholar 

  • Patil P, Dong Q et al (2019) Systemic clearance of p16(INK4a)-positive senescent cells mitigates age-associated intervertebral disc degeneration. Aging Cell 18(3):e12927

    Article  Google Scholar 

  • Piekarz KM, Bhaskaran S et al (2020) Molecular changes associated with spinal cord aging. Geroscience 42(2):765–784

    Article  CAS  Google Scholar 

  • Pla-Prats C, Thoma NH (2022) Quality control of protein complex assembly by the ubiquitin-proteasome system. Trends Cell Biol 32(8):696–706

    Article  CAS  Google Scholar 

  • Press M, Jung T et al (2019) Protein aggregates and proteostasis in aging: amylin and beta-cell function. Mech Ageing Dev 177:46–54

    Article  CAS  Google Scholar 

  • Rentscher KE, Carroll JE et al (2020) Relationship closeness buffers the effects of perceived stress on transcriptomic indicators of cellular stress and biological aging marker p16(INK4a). Aging 12(16):16476–16490

    Article  CAS  Google Scholar 

  • Roberts JA, Varma VR et al (2021) A brain proteomic signature of incipient Alzheimer’s disease in young APOE epsilon4 carriers identifies novel drug targets. Sci Adv 7(46):eabi8178

    Article  CAS  Google Scholar 

  • Salminen A, Kaarniranta K et al (2021) Insulin/IGF-1 signaling promotes immunosuppression via the STAT3 pathway: impact on the aging process and age-related diseases. Inflamm Res 70(10–12):1043–1061

    Article  CAS  Google Scholar 

  • Shetty GA, Hattiangady B et al (2013) Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus. Age (Dordr) 35(6):2165–2176

    Article  Google Scholar 

  • Shu J, Fang XH et al (2022) Microglia-induced autophagic death of neurons via IL-6/STAT3/miR-30d signaling following hypoxia/ischemia. Mol Biol Rep 49(8):7697–7707

    Article  CAS  Google Scholar 

  • Stenudd M, Sabelstrom H et al (2022) Identification of a discrete subpopulation of spinal cord ependymal cells with neural stem cell properties. Cell Rep 38(9):110440

    Article  CAS  Google Scholar 

  • Sun-Wang JL, Ivanova S et al (2020) The dialogue between the ubiquitin-proteasome system and autophagy: implications in ageing. Ageing Res Rev 64:101203

    Article  CAS  Google Scholar 

  • Talma N, Gerrits E et al (2021) P16-expressing microglial cells with distinct transcriptional profiles accumulate in the aging brain. Glia 69:E262–E263

    Google Scholar 

  • Tejeda G, Ciciriello AJ et al (2021) Biomaterial strategies to bolster neural stem cell-mediated repair of the central nervous system. Cells Tissues Organs. https://doi.org/10.1159/000515351

    Article  Google Scholar 

  • Wang CY, Fu JQ et al (2019a) Bartonella quintana type IV secretion effector BepE-induced selective autophagy by conjugation with K63 polyubiquitin chain. Cell Microbiol 21(4):e12984

    Article  Google Scholar 

  • Wang Z, Huang J et al (2019b) BAF45D Downregulation in spinal cord ependymal cells following spinal cord injury in adult rats and its potential role in the development of neuronal lesions. Front Neurosci 13:1151

    Article  Google Scholar 

  • Wu XF, Karin M (2015) Emerging roles of Lys63-linked polyubiquitylation in immune responses. Immunol Rev 266(1):161–174

    Article  CAS  Google Scholar 

  • Yu G, Hyun S (2021) Proteostasis-associated aging: lessons from a Drosophila model. Genes Genomics 43(1):1–9

    Article  Google Scholar 

  • Zhao HY, Zhang ST et al (2019) Long non-coding RNA GAS5 promotes PC12 cells differentiation into Tuj1-positive neuron-like cells and induces cell cycle arrest. Neural Regen Res 14(12):2118–2125

    Article  CAS  Google Scholar 

  • Zhou Z, Zhu X et al (2020) K63 ubiquitin chains target NLRP3 inflammasome for autophagic degradation in ox-LDL-stimulated THP-1 macrophages. Aging (Albany, NY) 12(2):1747–1759

    Article  CAS  Google Scholar 

  • Zhou SM, Zhong ZF et al (2021) IL-6/STAT3 induced neuron apoptosis in hypoxia by downregulating ATF6 expression. Front Physiol 12:729925

    Article  Google Scholar 

Download references

Acknowledgements

We thank the Center for Scientific Research of Anhui Medical University for valuable help in our experiment. We thank support from the General Experimental Center of School of Basic Medical Sciences.

Funding

This work was supported by The Natural Science Foundation of Anhui Province (2008085MH251); The Key Research and Development Project of Anhui Province (202004J07020037); Research project of Anhui Provincial Institute of Translational Medicine (2021zhyx-C19).

Author information

Author notes

  1. Tianyi Zhao and Chang Liu have contributed equally to this study.

Authors and Affiliations

  1. Department of Histology and Embryology, School of Basic Medical Sciences, Institute of Stem Cell and Tissue Engineering, Anhui Medical University, 81 Meishan Road, Hefei, 230032, Anhui, China

    Tianyi Zhao, Xinmeng Wang & Chao Liu

  2. Department of Orthopedics and Spine Surgery, The First Affiliated Hospital, Anhui Medical University, Hefei, 230032, Anhui, China

    Chang Liu

  3. Institute of Clinical Pharmacology, Anhui Medical University, Hefei, 230032, Anhui, China

    Lihua Liu

Authors
  1. Tianyi Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lihua Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xinmeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chao Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Tianyi Zhao wrote the manuscript and performed data curation, formal analysis, validation, investigation, visualization, and methodology. Chang Liu provided methodology, resources and funding. Lihua Liu provided resources and project administration. Xinmeng Wang provided methodology and investigation. Chao Liu wrole the manuscript, performed conceptualization, data curation, formal analysis, validation, investigation, visualization, methodology, supervision, administration, and provided funding. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Chao Liu.

Ethics declarations

Conflict of interest

The authors declare no competing financial and non-financial interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 486 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhao, T., Liu, C., Liu, L. et al. Aging-accelerated differential production and aggregation of STAT3 protein in neuronal cells and neural stem cells in the male mouse spinal cord. Biogerontology 24, 137–148 (2023). https://doi.org/10.1007/s10522-022-10004-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-022-10004-z

Keywords

Search

Navigation