Journal
MECHANISMS OF AGEING AND DEVELOPMENT
Volume 190, Issue -, Pages -Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.mad.2020.111296
Keywords
ATM; Ataxia-telangiectasia; Autophagy; hiPSCs; Mitophagy; Neural progenitors; Senescence; Oxidative stress
Categories
Funding
- National Science Centre [2012/07/B/NZ3/02180]
Ask authors/readers for more resources
ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A-Telangiectasia disease (A-T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A-T, we have focused on senescence of neural progenitor cells (NPCs) derived from A-T reprogrammed fibroblasts. Accordingly, A-T NPCs obtained through neural differentiation of iPSCs in 5% oxygen possessed some features of senescence including increased activity of SA-beta-gal and secretion of IL6 and IL8 in comparison to control NPCs. This phenotype of A-T NPC was accompanied by elevated oxidative stress. A-T NPCs exhibited symptoms of impaired autophagy and mitophagy with lack of response to chloroquine treatment. Additional sources of oxidative stress like increased oxygen concentration (20 %) and H2O2 respectively aggravated the phenotype of senescence and additionally disturbed the process of mitophagy. In both cases only A-T NPCs reacted to the treatment. We conclude that oxidative stress may be responsible for the phenotype of senescence and impairment of autophagy in A-T NPCs. Our results point to senescent A-T cells as a potential therapeutic target in this disease.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available