Funktion von Etherlipiden
Final Report Abstract
The work of this project demonstrates the importance of ELs for development, structure and function of the mouse CMS. Multiple phenotypes were observed in the EL-deficient cerebellum including defects in foliation and myelination,altered septate-like junctions, formation of axonal swellings, reduced nerve conduction velocity and disturbed PC innervation. Targeting and function of LRM-localized proteins might contribute to the formation of these phenotypes, as in thymocytes of about 25% of EL-deficient mice endogenous Thy-1 was not targeted to the surface suggesting peroxisomal EL synthesis to be essential for targeting of those GPI-APs that contain an alkyl chain at the sn-1 position of the PI moiety. The fact that only a limited number of EL-deficient animals showed this phenotype suggests genetic background variations and the ability of some of the animals to compensate for the lack of ELs. On isolated synaptosomes we observed an about 60% reduction of Ca2+-dependent glutamate and acetylcholine release. Although respiratory activity and intrasynaptosomal ATP were reduced by about 20%, this reduction seems not to be responsible for the observed decrease in transmitter release. Preliminary experiments using the Ca2+ ionophore ionomycin in the presence and absence (1mM EGTA) of extracellular Ca2+ indicated enhanced (about 50%) Ca2+ release from intrasynaptosomal Ca2+ stores of ELdeficient synaptosomes suggesting disturbance of intrasynaptosomal Ca2+ homeostasis. The observed formation of axonal swellings accumulating IP3R-rich smooth ER tubuli lends further support to the idea that Ca2+ homeostasis might be altered in the EL-deficient neural tissue. Further studies are necessary to resolve questions related to the physiological role of ELs. According to the results produced by this project, future studies should focus on targeting, localization and function of alkyl/acyl type GPI-APs as well as on the understanding on a molecular base of the reduced release of transmitters in EL-deficient nerve terminals particularly emphasizing changes in Ca2+ homeostasis and membrane fusion.
Publications
- Gorgas, K., et al. (2006) The ether lipid-deficient mouse: Tracking down plasmalogen functions. BBAMCR 1763, 1511-1526.
