Display options
Cite
Gorostieta-Salas E, Moreno-Blas D, Gerónimo-Olvera C, et al. Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain. Oxid Med Cell Longev. 2021;2021:6682336doi: 10.1155/2021/6682336.
Gorostieta-Salas, E., Moreno-Blas, D., Gerónimo-Olvera, C., Cisneros, B., Court, F. A., & Castro-Obregón, S. (2021). Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain. Oxidative medicine and cellular longevity, 20216682336. https://doi.org/10.1155/2021/6682336
Gorostieta-Salas, Elisa, et al. "Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain." Oxidative medicine and cellular longevity vol. 2021 (2021): 6682336. doi: https://doi.org/10.1155/2021/6682336
Gorostieta-Salas E, Moreno-Blas D, Gerónimo-Olvera C, Cisneros B, Court FA, Castro-Obregón S. Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain. Oxid Med Cell Longev. 2021 Aug 13;2021:6682336. doi: 10.1155/2021/6682336. eCollection 2021. PMID: 34434486; PMCID: PMC8382534.
Copy Download .nbib Format: NLM
Share it on

Oxid Med Cell Longev. 2021 Aug 13;2021:6682336. doi: 10.1155/2021/6682336. eCollection 2021.

Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain.

Oxidative medicine and cellular longevity

Elisa Gorostieta-Salas, Daniel Moreno-Blas, Cristian Gerónimo-Olvera, Bulmaro Cisneros, Felipe A Court, Susana Castro-Obregón

Affiliations

  1. Departamento de Neurodesarrollo y Fisiología, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
  2. Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.
  3. Department of Genetics and Molecular Biology, Center of Research and Advanced Studies (CINVESTAV-IPN), Mexico City, Mexico.
  4. Fondap Geroscience Center for Brain in Health and Metabolism, Santiago, Chile.
  5. Buck Institute for Research on Aging, Novato, USA.

PMID: 34434486 PMCID: PMC8382534 DOI: 10.1155/2021/6682336

Abstract

Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson-Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-

Copyright © 2021 Elisa Gorostieta-Salas et al.

Conflict of interest statement

The authors declare that they have no conflict of interest.

References

  1. Nat Protoc. 2009;4(12):1798-806 - PubMed
  2. Aging Cell. 2019 Feb;18(1):e12847 - PubMed
  3. Cell. 2014 Nov 6;159(4):709-13 - PubMed
  4. Nat Cell Biol. 2012 Sep;14(9):924-34 - PubMed
  5. Nat Rev Neurosci. 2001 Jan;2(1):51-61 - PubMed
  6. Neurosci Biobehav Rev. 2017 Aug;79:66-86 - PubMed
  7. J Cell Physiol. 2004 May;199(2):157-70 - PubMed
  8. Nature. 2015 Sep 3;525(7567):56-61 - PubMed
  9. Aging Cell. 2019 Apr;18(2):e12901 - PubMed
  10. Nature. 2018 Oct;562(7728):578-582 - PubMed
  11. Ageing Res Rev. 2016 Aug;29:1-12 - PubMed
  12. Stem Cell Investig. 2019 Feb 25;6:6 - PubMed
  13. Autophagy. 2015 Nov 2;11(11):2014-2032 - PubMed
  14. J Gerontol A Biol Sci Med Sci. 2016 Jan;71(1):50-60 - PubMed
  15. Transl Neurodegener. 2020 Jul 3;9(1):25 - PubMed
  16. Nat Rev Mol Cell Biol. 2020 Aug;21(8):439-458 - PubMed
  17. Cell Rep. 2018 May 15;23(7):1915-1921 - PubMed
  18. Mol Cancer Ther. 2014 Mar;13(3):675-86 - PubMed
  19. Int J Cancer. 2012 Apr 15;130(8):1715-25 - PubMed
  20. Exp Cell Res. 2020 May 1;390(1):111927 - PubMed
  21. J Biol Chem. 2004 Jul 2;279(27):28574-84 - PubMed
  22. Annu Rev Pathol. 2010;5:99-118 - PubMed
  23. Aging Cell. 2019 Oct;18(5):e13002 - PubMed
  24. Cell. 2013 Jun 6;153(6):1194-217 - PubMed
  25. Biochem Soc Trans. 2019 Aug 30;47(4):1157-1164 - PubMed
  26. Nat Commun. 2018 Aug 17;9(1):3312 - PubMed
  27. Science. 2018 Mar 16;359(6381):1277-1283 - PubMed
  28. Curr Biol. 2016 Jan 11;26(1):129-36 - PubMed
  29. Aging Cell. 2016 Jun;15(3):416-27 - PubMed
  30. J Gerontol A Biol Sci Med Sci. 1998 Jul;53(4):B235-9 - PubMed
  31. Exp Neurobiol. 2019 Dec 31;28(6):643-657 - PubMed
  32. Autophagy. 2016;12(2):245-60 - PubMed
  33. Traffic. 2020 Jan;21(1):60-75 - PubMed
  34. Cell Rep. 2014 Oct 9;9(1):180-192 - PubMed
  35. Autophagy. 2019 Apr;15(4):631-651 - PubMed
  36. Front Aging Neurosci. 2021 Feb 25;13:646924 - PubMed
  37. Aging (Albany NY). 2019 Aug 30;11(16):6175-6198 - PubMed
  38. Nature. 2016 Jan 7;529(7584):37-42 - PubMed
  39. Aging Cell. 2020 Jan;19(1):e13071 - PubMed
  40. Nat Rev Mol Cell Biol. 2007 Sep;8(9):692-702 - PubMed
  41. Cell Death Dis. 2019 Feb 6;10(2):107 - PubMed
  42. Mol Cell. 2012 Dec 14;48(5):667-80 - PubMed
  43. Cell Rep. 2019 Jan 15;26(3):582-593.e5 - PubMed
  44. Neuron. 2017 Apr 5;94(1):93-107.e6 - PubMed
  45. Biochem J. 2017 Jan 15;474(2):281-300 - PubMed
  46. Science. 2011 Jun 17;332(6036):1429-33 - PubMed

Publication Types