hippocampus; stem cell; depression; neurogenesis; disease modeling; metabolism
Knobloch Marlen, Pilz Gregor-Alexander, Ghesquière Bart, Kovacs Werner J, Wegleiter Thomas, Moore Darcie L, Hruzova Martina, Zamboni Nicola, Carmeliet Peter, Jessberger Sebastian (2017), A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity., in Cell reports
, 20(9), 2144-2155.
Beckervordersandforth Ruth, Ebert Birgit, Schäffner Iris, Moss Jonathan, Fiebig Christian, Shin Jaehoon, Moore Darcie L, Ghosh Laboni, Trinchero Mariela F, Stockburger Carola, Friedland Kristina, Steib Kathrin, von Wittgenstein Julia, Keiner Silke, Redecker Christoph, Hölter Sabine M, Xiang Wei, Wurst Wolfgang, Jagasia Ravi, Schinder Alejandro F, Ming Guo-Li, Toni Nicolas, Jessberger Sebastian, Song Hongjun, Lie D Chichung (2017), Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis., in Neuron
, 93(6), 1518-1518.
Moore Darcie, Jessberger Sebastian (2017), Creating Age Asymmetry: Consequences of Inheriting Damaged Goods in Mammalian Cells, in CellPress
Knobloch Marlen, Jessberger Sebastian (2017), Current Opinion in Neurobiology, in Elsevier
Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in discrete areas of the mammalian brain. This process, called adult neurogenesis, is critical for tissue homeostasis and adult-brain function. Furthermore, altered or failing neurogenesis has been associated with a number of neuro-psychiatric diseases such as major depression and age-related cognitive decline. To ensure the life-long generation of newborn neurons, the activity of NSPCs is tightly controlled by a number of extrinsic and intrinsic mechanisms. We have previously identified a critical role for specialized lipid metabolism in NSPCs that is required for the proper generation of new neurons in the adult mouse brain. With the program proposed here I aim i) to investigate the nature and fate of lipids in NSPCs and to characterize the cell-cycle associated dynamics of lipid storage organelles using diverse tools incl. time-lapse confocal microscopy and lipidomics, ii) to analyse the role of lipid-associated signalling (e.g., post-translational modifications of proteins by palmitoylation) and their dependency on newly-synthesized fatty acids using candidate-based and unbiased strategies, iii) to test if enhancement of de novo lipogenesis in NSPCs is sufficient to increase neurogenesis and ameliorate disease symptoms in animal models of major depression, which may lead to the validation of a novel molecular target to treat neurogenesis-associated diseases, iv) to evaluate the role of fatty acid synthase (Fasn), the key enzyme of de novo lipogenesis, as a putative new mediator of human cognition by generating a mouse model of human disease and targeting human embryonic stem cells. The insights gained from the studies proposed here have the potential to substantially advance our understanding of adult NSPC biology, to identify a new molecular target to treat neurogenesis-associated disease, and to create a novel link between adult neurogenesis and cognitive dysfunction.