Hypoxia and Sirtuin 1, two factors linking DNA damage and differentiation in neural stem/ progenitor cells

Background: The redox state of the cells determines cell fate in many ways, including the decision between self-renewal and differentiation. Neural stem/progenitor cells (NSPCs) are typically located in hypoxic niches. Before/during differentiation, NSPCs migrate out of these niches indicating induction of differentiation under more oxidizing conditions. Our own data demonstrate a redox-dependent role of Sirtuin 1 (Sirt1), a protein de-acetylase, in differentiation of NSPCs and redox-dependent activity of Sirt1.

Aim: The project aims at the characterization of the molecular pathways guaranteeing the fine balance of oxidizing conditions allowing differentiation but inhibiting DNA damage. We are interested in the identification of molecular switches controlling neural differentiation, which is of high importance for translational research investigating improvement of adult regeneration after primary or secondary (e.g. inflammatory) neurodegeneration.

Experimental procedure / working programme: Our experimental programme follows in the general aims this project. 1) Genotoxic substances will be applied to quiescent or active NSPCs isolated from wildtype and Sirt1-deficient mice to compare their capacities in self-renewal, differentiation, proliferation, and DNA protection. 2) Using organotypic slice cultures and microscopy of adult brains of these two mouse lines, we will investigate the role of Sirt1 in generation/protection/differentiation of NSPCs in adult mice, which has an important impact on regeneration of neurological diseases. 3) We will identify and compare the redox state of Sirt1 in self-renewing and differentiating NSPCs with and without applying hypoxia or other genotoxins via e.g. mass spectroscopy. In addition, redox-regulation of Sirt1 interaction partners and Sirt1-dependent pathways and its contribution to repair or protect against DNA damage will be investigated. In close cooperation with other members of the GRK 2578, our data will be translated to the human system and we will include further Sirt1-dependent pathways such as autophagy.

Recent publications:

1. Prozorovski T, Schulze-Topphoff U, Glumm R, Baumgart J, Schröter F, Ninnemann O, Siegert E, Bendix I, Brüstle O, Nitsch R, Zipp F, Aktas O (2008). Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 10, 385-394
2. Bräutigam L, Jensen LD, Poschmann G, Nyström S, Bannenberg S, Dreij K, Lepka K, Prozorovski T, Montano SJ, Aktas O, Uhlén P, Stühler K, Cao Y, Holmgren A, Berndt C (2013). Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1. Proc Natl Acad USA 110, 20057-20062
3. Prozorovski T, Schneider R, Berndt C, Hartung HP, Aktas O (2015). Redox-regulated fate of neural stem progenitor cells. Biochim Biophys Acta - Gen Subjects 1850,1543-1554
4. Sies, H., Berndt, C., and Jones D.P (2017). Oxidative Stress. Annu. Rev. Biochem. 86: 715-7484.
5. Prozorovski T, Ingwersen J, Lukas D, Göttle P, Graf J, Schneider R, Franke K, Schumacher S, Britsch S, Hartung H-P, Küry P, Berndt C, Aktas O (2019). Regulation of sirtuin expression in autoimmune neuroinflammation: Induction of SIRT1 in oligodendrocyte progenitor cells. Neurosci Lett 704 116-125