ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy.

Abstract 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-β-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.