"This study is the first to show that lowering the levels of this lipid in nerve terminals affects the efficiency of neurotransmission," said senior author, Pietro De Camilli, Eugene Higgins Professor of Cell Biology and a Howard Hughes Medical Institute investigator.
De Camilli's laboratory has extensively studied the mechanism underlying cycling of synaptic vesicles, the small sacs containing neurotransmitters that exchange information between neurons. Synaptic vesicles release their contents at junctions between nerve terminals by fusing with the plasma membrane where they rapidly re-internalize, reload with neurotransmitter, and are reused.
The researchers genetically engineered laboratory mice lacking the enzyme PIPK1-gamma at the synapse. This enzyme plays a major role in the synthesis of PtdIns(4,5)P2, a member of a class of lipids called phosphoinositides. The mice born without PIPK1-gamma were apparently normal, but they were unable to feed and died quickly. Studies of their nervous system revealed lower levels of PtdIns(4,5)P2 and a partial impairment both of the process of fusion of synaptic vesicles as well as of their recycling.
De Camilli said these studies provide new insight into basic mechanisms in synaptic transmission, but also have implications for medicine. For example, Down syndrome patients have an extra copy of the gene encoding the enzyme synaptojanin 1, which degrades PtdIns (4,5)P2 in the brain. Patients with Lowe syndrome, who also have mental retardation, lack another PtdIns(4,5)P2 degrading enzyme. Cancer and diabetes also can result from abnormal metabolism of phosphoinositides, De Camilli said.
"Typically, studies of synaptic transmission have focused on membrane proteins," said De Camilli. "Only recently has the importance of the chemistry of membrane lipids and of their metabolism started to be fully appreciated. The field is still in its infancy, but rapid advancements in the methodology for the analysis of lipids promise major progress in the field and the possibility of identifying new targets for therapeutic interventions in human diseases."
De Camilli's team includes Gilbert Di Paolo, Markus Wenk, Sergey Voronov, and Masanori Obayashi. Other authors are Richard Flavell, Reiko Fitzsimonds, and Keith Gipson, all of Yale, and Timothy Ryan and Howard Moskovitz of Weill Cornell Medical College in New York City. The study was funded by grants from the National Institutes of Health, the Yale Center for Genomics and Proteomics and the Howard Hughes Medical Institute.
Citation: Nature, September 23, 2004
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