Research highlight: Signaling lipids and neuronal communication

Weisman lab outlines the manufacturing and roles of two key lipids in the brain

Researchers have outlined the mechanisms by which the brain makes two important signaling lipids and determined what roles those lipids play in neuronal communication. Improper levels of the lipids can cause severe neurological problems, such as a type of Charcot-Marie-Tooth disorder, one of the most common hereditary neurological disorders, and some motor neuron diseases, including some cases of amyotrophic lateral sclerosis (also called Lou Gehrig’s disease).

Lois Weisman in the Life Sciences Institute at the University of Michigan identified the protein responsible for one of the two lipids: a protein called Pikfyve. A team lead by Sergey Zolov, a post-doctoral fellow in Wesiman’s lab, found that Pikfyve was the sole protein responsible for a signaling lipid known as phosphatidylinositol 3,5-bisphosphate, or PI(3,5)P2, which in turn generates another signaling lipid, called phosphatidylinositol-5-phosphate, or PI5P. Their paper, published recently in the Proceedings of the National Academy of Science, also draws a direct link between the two signaling lipids and neurological disease; diseases previously attributed only to low levels of PI(3,5)P2 might actually be caused by low levels of either or both of the two lipids.

The researchers also linked lipid levels to degeneration in the heart, lungs, kidney, thymus and spleen. “All tissues tested were affected,” Zolov said. “Before, we only knew about defects in the nervous system.”

While Zolov and his team where outlining the pathway for creating the lipids, another group was examining those lipids’ role in regulation of communication in the brain. “One of the roles of the signaling lipids [PI(3,5)P2 and PI5P] is to keep things relatively quiet in the synapses,” said Amber McCartney, a graduate student in the lab of Michael Sutton of the Molecular and Behavioral Neuroscience Institute at U-M who collaborated with Weisman.

McCartney is the co-lead author on a July 2012 paper that explained the role of the protein VAC14—another regulator of PI(3,5)P2 and PI5P—in regulating post-synaptic function, where a synapse receives signals from a neuron. The paper suggests VAC14 might be connected to epilepsy and some learning disorders.

The paper by Zolov, et al., titled “In vivo, Pikfyve generates PI(3,5)P2, which serves as both a signaling lipid and the major precursor for PI5P,” was published Oct. 8 in the Proceedings of the National Academy of Sciences. The article can be found here.

The paper by Yanling Zhang, McCartney, et al. is titled “Modulation of synaptic function by VAC14, a protein that regulates the phosphoinositides PI(3,5)P2 and PI5P”and was published by The EMBO Journal on July 27. The article can be found here.