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Nenad Suknovic

PhD Student in Regeneration

  • T: +41 22 379 67 99
  • office 4055a (Sciences III)
  • The ULK1 kinase, a necessary component of the pro-regenerative and anti-aging machinery in Hydra. Mech Ageing Dev 2020 Dec;():111414. S0047-6374(20)30210-4. 10.1016/j.mad.2020.111414.

    abstract

    Hydra vulgaris (Hv) has a high regenerative potential and negligible senescence, as its stem cell populations divide continuously. In contrast, the cold-sensitive H. oligactis (Ho_CS) rapidly develop an aging phenotype under stress, with epithelial stem cells deficient for autophagy, unable to maintain their self-renewal. Here we tested in aging, non-aging and regenerating Hydra the activity and regulation of the ULK1 kinase involved in autophagosome formation. In vitro kinase assays show that human ULK1 activity is activated by Hv extracts but repressed by Ho_CS extracts, reflecting the ability or inability of their respective epithelial cells to initiate autophagosome formation. The factors that keep ULK1 inactive in Ho_CS remain uncharacterized. Hv_Basel1 animals exposed to the ULK1 inhibitor SBI-0206965 no longer regenerate their head, indicating that the sustained autophagy flux recorded in regenerating Hv_AEP2 transgenic animals expressing the DsRed-GFP-LC3A autophagy tandem sensor is necessary. The SBI-0206965 treatment also alters the contractility of intact Hv_Basel1 animals, and leads to a progressive reduction of animal size in Hv_AEP2, similarly to what is observed in ULK1(RNAi) animals. We conclude that the evolutionarily-conserved role of ULK1 in autophagy initiation is crucial to maintain a dynamic homeostasis in Hydra, which supports regeneration efficiency and prevents aging.

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  • Deficient autophagy in epithelial stem cells drives aging in the freshwater cnidarian . Development 2019 Dec;():. dev.177840. 10.1242/dev.177840.

    abstract

    possesses three distinct stem cell populations that continuously self-renew and prevent aging in However sexual animals from the cold-sensitive ( strain develop an aging phenotype upon gametogenesis induction, initiated by the loss of interstitial stem cells. Animals stop regenerating, lose their active behaviors and die within three months. This phenotype is not observed in the cold-resistant strain. To dissect the mechanisms of aging we compared the self-renewal of epithelial stem cells in these two strains and found it irreversibly reduced in aging while sustained in non-aging We also identified a deficient autophagy in epithelial cells, with a constitutive deficiency in autophagosome formation as detected with the mCherry-eGFP-LC3A/B autophagy sensor, an inefficient response to starvation as evidenced by the accumulation of the autophagosome cargo protein p62/SQSTM1, and a poorly-inducible autophagy flux upon proteasome inhibition. In the non-aging animals, the blockade of autophagy by knocking-down suffices to induce aging. This study highlights the essential role of a dynamic autophagy flux to maintain epithelial stem cell renewal and prevent aging.

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