A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype

Veronica Porterfield, Shahzad S. Khan, Erin P. Foff, Mehmet Murat Koseoglu, Isabella K. Blanco, Sruthi Jayaraman, Eric Lien, Michael J. McConnell, George S. Bloom, John S. Lazo, Elizabeth R. Sharlow

Research output: Contribution to journalArticle

Abstract

A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells. We demonstrated that C9+ and neurotypic neuronal progenitor cells differentiate into neurons. The C9+ neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9+ neurons. Moreover, C9+ neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9+ neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.

Original languageEnglish (US)
Pages (from-to)125-134
Number of pages10
JournalNeurobiology of Aging
Volume90
DOIs
StatePublished - Jun 2020
Externally publishedYes

Keywords

  • Amyotrophic lateral sclerosis
  • Cell cycle re-entry
  • Frontotemporal dementia
  • Senescence
  • Senescence-associated secretory phenotype

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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  • Cite this

    Porterfield, V., Khan, S. S., Foff, E. P., Koseoglu, M. M., Blanco, I. K., Jayaraman, S., Lien, E., McConnell, M. J., Bloom, G. S., Lazo, J. S., & Sharlow, E. R. (2020). A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype. Neurobiology of Aging, 90, 125-134. https://doi.org/10.1016/j.neurobiolaging.2020.02.011