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Elucidating the Role of Lipid Metabolism for Life-long Neurogenesis in the Mammalian Brain

English title Elucidating the Role of Lipid Metabolism for Life-long Neurogenesis in the Mammalian Brain
Applicant Jessberger Sebastian
Number 157859
Funding scheme Temporary Backup Schemes
Research institution Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.07.2015 - 30.06.2020
Approved amount 1'746'842.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Cellular Biology, Cytology

Keywords (6)

hippocampus; stem cell; depression; neurogenesis; disease modeling; metabolism

Lay Summary (German)

Lead
Neurale Stammzellen produzieren lebenslang neue Nervenzellen in bestimmten Hirnregionen (adulte Neurogenese). Dieser Prozess ist wichtig für bestimmte Lern- und Gedächtnisprozessen und eine reduzierte bzw. veränderte Neurogenese ist assoziiert mit einer Reihe von neuropsychiatrischen Erkrankungen (z.B. mit Depressionen und Epilepsie). Die Aktivität von neuralen Stammzellen wird durch einen spezialisierten zellulären Metabolismus reguliert. Im Rahmen des vorliegenden Projektes soll untersucht werden, welche metabolischen Veränderungen von der Stammzelle zur neugeborenen Nervenzelle stattfinden und ob allenfalls Signalwege therapeutisch nutzbar gemacht werden können - etwa um im Tiermodell bei Depressionen die Neurogenese zu erhöhen. Ausserdem ist es Ziel herausfinden, inwiefern ein veränderter, stammzell-assozierter Zellmetabolismus bei kognitiven Prozessen im menschlichen Gehirn eine Rolle spielt.
Lay summary

 

Neurale Stammzellen im Gehirn produzieren lebenslang neue Nervenzellen. Dieser Prozess, adulte Neurogenese genannt, ist wichtig für verschiedene Formen von Lernen und Gedächtnis. Zudem steht eine verringerte oder veränderte Neurogenese im Zusammenhang mit einer Vielzahl von neuropsychiatrischen Erkrankungen wie Depressionen und Epilepsie. Die molekularen Mechanismen, die der adulten Neurogenese zugrundeliegen, sind zum grössten Teil noch unbekannt. In früheren Arbeiten haben wir einen neuen Mechanismus entdeckt, der die Aktivität von neuralen Stammzellen über eine Regulation des zellulären Metabolismus steuert. Im Rahmen des vorliegenden Projektes soll untersucht werden, welche metabolischen Veränderungen von der Stammzelle zur neugeborenen Nervenzelle stattfinden und ob allenfalls Signalwege therapeutisch nutzbar gemacht werden können – etwa um im Tiermodell bei Depressionen die Neurogenese zu erhöhen. Ausserdem ist es Ziel herausfinden, inwiefern ein veränderter, stammzell-assozierter Zellmetabolismus bei kognitiven Prozessen im menschlichen Gehirn eine Rolle spielt.

Direct link to Lay Summary Last update: 24.02.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity.
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.
Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.
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.
Creating Age Asymmetry: Consequences of Inheriting Damaged Goods in Mammalian Cells
Moore Darcie, Jessberger Sebastian (2017), Creating Age Asymmetry: Consequences of Inheriting Damaged Goods in Mammalian Cells, in CellPress, 82.
Current Opinion in Neurobiology
Knobloch Marlen, Jessberger Sebastian (2017), Current Opinion in Neurobiology, in Elsevier, 45.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
BrainDisC Conference Bernstein Center Talk given at a conference Molecular and cellular mechanisms regulating neurogenesis 27.09.2016 Freiburg, Germany Jessberger Sebastian;
Bridges to the Future: German-Israeli Scientific Relations Talk given at a conference Molecular and cellular mechanisms regulating neurogenesis 21.09.2016 Tel Aviv, Israel Jessberger Sebastian;
12th European Congress on Epileptology Talk given at a conference Molecular and cellular mechanisms regulating neurogenesis 11.09.2016 Prague, Czech Republic Jessberger Sebastian;
3rd Neurogenesis Meeting Talk given at a conference Cell division in the adult brain 11.07.2016 Bordeaux, France Jessberger Sebastian;
5th Lugano Stem Cell Meeting Talk given at a conference Molecular and cellular control of neural stem cell activity 20.06.2016 Lugano, Switzerland Jessberger Sebastian;
6th International IZKF Symposium Talk given at a conference Stem cell aging and cell division 16.06.2016 Kloster Banz, Germany Jessberger Sebastian;
REMBO meeting (Can Tallada) Talk given at a conference Mechanisms of stem cell maintenance 08.06.2016 Girona, Spain Jessberger Sebastian;
Wyss Center Lecture Series Talk given at a conference Molecular and cellular mechanisms regulating neural stem cell activity 31.05.2016 Zürich, Switzerland Jessberger Sebastian;
What's New in Adult Neurogenesis?(College de France) Talk given at a conference A mechanism for asymmetric segregation of age in neural stem cells 19.05.2016 Paris, France Jessberger Sebastian;
Institut Pasteur Seminar series Talk given at a conference Molecular and cellular mechanisms regulating neural stem cell activity 22.04.2016 Paris, France Jessberger Sebastian;
ULB Interdisciplinary Seminars Talk given at a conference Mechanisms of Neurogenesis 14.04.2016 Brussels, Belgium Jessberger Sebastian;
EMBO sectorial meeting Tissue Morphogenesis Talk given at a conference Asymmetric cell division of neural stem cell 07.02.2016 Dresden, Germany Jessberger Sebastian;


Self-organised

Title Date Place
Fusion Conference: Neurogenesis: Implications for Lifelong Development and Disease 02.03.2016 Cancun, Mexico

Patents

Title Date Number Inventor Owner
Method for in-vitro Stem Cell Expansion 11.07.2017 uz267ep

Associated projects

Number Title Start Funding scheme
156943 Mechanisms and functional relevance of mitochondrial metabolism for adult neural stem cell activity 01.01.2015 Project funding (Div. I-III)
138335 Molekular Mechanismen Adulter Neurogenese 01.10.2011 Project funding (Div. I-III)

Abstract

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.
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