Study links Piezo1 and intracellular cholesterol levels during neuronal development

A new study led by the University of California, Irvine reveals how mechanical forces and tissue mechanics influence the morphology of the developing brain and establishes a direct link in neural stem cells between Piezo1, a mechanically activated ion channel, and intracellular cholesterol levels during neuronal development. development.

The study, titled “Piezo1 Regulates Cholesterol Biosynthesis to Influence Neural Stem Cell Fate During Brain Development,” was published today in the Journal of General Physiology. The study results demonstrate a role for Piezo1 in the neurodevelopmental process that modulates cell quantity, quality, and organization by influencing cellular cholesterol metabolism.

Our surprising discovery linking Piezo1 and cholesterol also motivates research on Piezo1 in neurodegenerative diseases linked to cholesterol homeostasis, such as Alzheimer’s disease. By controlling Piezo1 activity through therapeutics, we may be able to develop new treatments for some of these diseases.”


Medha Pathak, PhD, Assistant Professor, Department of Physiology and Biophysics at UCI School of Medicine

Neural development is a multi-step process that involves the orchestration of many complex events to generate the brain and spinal cord. As the brain develops, cells multiply and organize themselves into structures and connect with other cells. These processes produce mechanical forces that further shape the patterning of the brain, but how cells sense these mechanical signals is not fully understood.

“We have previously found that Piezo1 channels are activated in response to both externally applied and cell-generated mechanical forces in human fetal brain-derived neural stem/progenitor cells, and we now show in our current study that Piezo1 is important for proper brain development,” said Jamison Nourse, PhD, associate project scientist in the Department of Physiology and Biophysics and first author of the study. “Through our research, we have discovered a novel link between Piezo1 and cholesterol biosynthesis, which opens new avenues of investigation into how mechanical forces influence lipid metabolism in the brain.”

Previous research has established the role that the Piezo family of mechanically activated ion channels plays in mechanotransduction in many physiological systems, including vascular development, cardiovascular homeostasis, lymphatic development, red blood cell volume regulation, baroreceptor response in neurons, cartilage mechanics, bone formation. , macrophage polarization responses, keratinocyte migration in wound healing, and neural stem cell fate. In 2021, Dr. Ardem Patapoutian of the Scripps Research Institute in San Diego was awarded the Nobel Prize in Physiology or Medicine for the groundbreaking discovery of Piezo channels.

“Incorrect brain development can lead to lifelong malformations and functional defects,” Pathak said. “And, although we still don’t understand the reason behind many brain developmental defects, our work provides new approaches to understanding how brain defects can arise.”

Pathak and his research team continue to explore Piezo1 and its effect on cholesterol metabolism in early development of the human brain and in adult neurodegenerative diseases.

This work was funded by the National Institutes of Health.

Source:

University of California – Irvine

Journal reference:

Nourse, J.L. et al. (2022) Piezo1 regulates cholesterol biosynthesis to influence neural stem cell fate during brain development. Journal of General Physiology. doi.org/10.1085/jgp.202213084.

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