Zurich – An enzyme in fat metabolism controls the activity of brain stem cells and lifelong brain development. If the enzyme does not work correctly, this limits learning and memory performance in humans and mice, as researchers at the University of Zurich have determined. The regulation of stem cell activity via fat metabolism could lead to new therapies for brain diseases.
Neural stem cells are not only responsible for early brain development – they remain active for a lifetime. They divide and continuously form new nerve cells and enable the brain to continuously adapt to new requirements. Various genetic changes impair the activity of neural stem cells and thus lead to impaired learning and memory performance in affected people. So far, little has been known about the mechanisms responsible for this.
Enzyme regulates the activity of brain stem cells
An international research team led by Sebastian Jessberger, professor at the Institute of Brain Research at the University of Zurich (UZH), is now showing for the first time in a study published in Cell Stem Cell that an enzyme in fat metabolism regulates the lifelong activity of stem cells in the brain. This enzyme – the so-called fatty acid synthase (FASN) – is responsible for the formation of fatty acids. A specific mutation in the genetic information of the enzyme restricts cognitive performance in affected patients.
Led by postdoc Megan Bowers and PhD students Tong Liang and Daniel Gonzalez-Bohorquez, the researchers examined the genetic modification of FASN both in the mouse model and in human brain organoids – organ-like cell cultures of the brain that are formed by human embryonic stem cells. “This approach enables the effects of the defective enzyme in the brain of adult mice and during early human brain development to be analyzed in parallel,” explains Jessberger. For this purpose, the genetic makeup of mice and human organoids was experimentally modified so that the enzyme of fat metabolism has exactly the mutation that was found in people with cognitive deficits.
Decreased stem cell activity reduces cognitive performance
Both in the mouse and in human tissue, the FASN mutation led to a reduced division of stem cells, which continuously form new nerve cells. This is due to the overactivity of the mutated enzyme: this causes fats to accumulate inside the cell, which puts the stem cells under stress and reduces their ability to divide. Similar to the cognitive loss of affected people, the mice also showed learning and memory restrictions due to the mutation. “Our results provide evidence of the functional relationship between fat metabolism, stem cell activity and cognitive performance,” summarizes Jessberger.
The mechanism now identified shows how fat metabolism regulates the activity of neuronal stem cells and thus influences brain development. “Only the linking of research in animal models and on human cells has enabled the new findings on learning and memory restrictions in humans,” emphasizes Jessberger. According to the scientists, their methodology represents a “blueprint” for researching the activity of brain stem cells and their role in cognitive processes in detail, thereby better understanding poorly understood diseases.
Stem cells as a therapeutic target for brain diseases
“We also hope to be able to control stem cell activity therapeutically in the future so that it can also be used to repair the brain – for example, for the treatment of cognitive diseases or diseases in which nerve cells die, such as Parkinson’s disease or Alzheimer’s,” says Sebastian Jessberger. (University of Zurich / mc / ps)
Literature:
Megan Bowers, Tong Liang, Daniel Gonzalez-Bohorquez, Sara Zocher, Baptiste N. Jaeger, Werner J. Kovacs, Clemens Röhrl, Kaitlyn ML Cramb, Jochen Winterer, Merit Kruse, Slavica Dimitrieva, Rupert W. Overall, Thomas Wegleiter, Hossein Najmabadi , Clay F. Semenkovich, Gerd Kempermann, Csaba Földy, Sebastian Jessberger. FASN-dependent lipid metabolism links neurogenic stem / progenitor cell activity to learning and memory deficits. Cell stem cell. 7 May 2020. DOI: 10.1016 / j.stem.2020.04.002
financing
The research was supported by an SNSF Consolidator Grant from the Swiss National Science Foundation, the European Research Council, the Dr. Eric Slack-Gyr Foundation, the Betty & David Koetser Foundation, the Center for Neuroscience Zurich and a research grant from the University of Zurich.
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