TY - JOUR
T1 - A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype
AU - Porterfield, Veronica
AU - Khan, Shahzad S.
AU - Foff, Erin P.
AU - Koseoglu, Mehmet Murat
AU - Blanco, Isabella K.
AU - Jayaraman, Sruthi
AU - Lien, Eric
AU - McConnell, Michael J.
AU - Bloom, George S.
AU - Lazo, John S.
AU - Sharlow, Elizabeth R.
N1 - Publisher Copyright:
© 2020 Elsevier Inc.
PY - 2020/6
Y1 - 2020/6
N2 - 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.
AB - 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.
KW - Amyotrophic lateral sclerosis
KW - Cell cycle re-entry
KW - Frontotemporal dementia
KW - Senescence
KW - Senescence-associated secretory phenotype
UR - http://www.scopus.com/inward/record.url?scp=85081655584&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85081655584&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2020.02.011
DO - 10.1016/j.neurobiolaging.2020.02.011
M3 - Article
C2 - 32184029
AN - SCOPUS:85081655584
SN - 0197-4580
VL - 90
SP - 125
EP - 134
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -