Nervous System Defect Linked to Lipid Deficiency

Researchers have found that synthesis of the membrane lipid phosphatidylinositol-4,5-bisphosphate (PtdIns[4,5]P2) in synaptic vesicles plays a critical role in the regulation of multiple steps of the synaptic vesicle cycle and ultimately in how messages are passed from the brain to the nervous system.

Investigators at Yale University (New Haven, CT, USA; www.yale.edu) worked with a line of mice that had been genetically engineered to lack the gene for the enzyme PIPK1-gamma in their synaptic vesicles. This enzyme is required for the synthesis of PtdIns(4,5)P2.

Results published in the September 23, 2004, issue of Nature revealed that the mice with decreased PtdIns(4,5)P2 developed defective synaptic vesicles that led to their deaths shortly after birth. Defects included decreased frequency of miniature currents, enhanced synaptic depression, a smaller readily releasable pool of vesicles, delayed endocytosis, and slower recycling kinetics.

"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 Dr. Pietro De Camilli, professor of cell biology at Yale University. "Typically, studies of synaptic transmission have focused on membrane proteins. 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.”



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