Impaired neurotransmission in ether lipid-deficient nerve terminals.
Impaired neurotransmission in ether lipid-deficient nerve terminals.
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DOI：
10.1093/hmg/dds097
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发表时间：
2012-06-15
影响因子：
3.5
通讯作者：
Just WW
中科院分区：
文献类型：
--
作者：
Brodde A;Teigler A;Brugger B;Lehmann WD;Wieland F;Berger J;Just WW
分离的醚脂（EL）生物合成缺陷在人类中引起2型和3型点状软骨发育不良，严重的过氧化物酶体疾病。使用先前描述的小鼠模型[Rodemer， C, Thai, t.p., Brugger， B., Kaercher， T., Werner， H., Nave, k.a., Wieland， F., Gorgas， K.和Just， W.W.(2003)]，醚脂质生物合成失活导致雄性不育，小鼠眼睛发育缺陷和视神经发育不全。嗡嗡声。摩尔,麝猫。[j], 12, 1881-1895]，我们研究了离体小鼠神经末梢（突触体）EL缺乏对神经递质（NTs）谷氨酸和乙酰胆碱突触前释放的影响。Ca2+依赖性胞吐和Ca2+非依赖性递质外排均受到影响。el缺陷突触体呼吸速率降低，腺苷-5 ' -三磷酸/二磷酸腺苷（ATP/ADP）比值降低。因此，atp驱动的过程，如突触囊泡循环和Na+、K+和Ca2+稳态的维持，可能会受到干扰。对EL缺乏的神经和非神经组织中的活性氧进行分析发现，哺乳动物中枢神经系统中最丰富的EL物质——质mallogens (PLs)，在很大程度上促进了脂质过氧化产物丙二醛的生成。尽管缺乏el的组织含有较少的脂质过氧化产物，但缺乏el的成纤维细胞更容易受到诱导氧化应激的影响。综上所述，这些结果表明，由于el缺乏组织的能量状态降低，NTs的Ca2+非依赖性外排增加，而Ca2+依赖性释放下降。此外，磷脂酰乙醇胺浓度的增加主要补偿了PLs的缺乏，并导致脑皮层和小脑中脂质过氧化产物水平显著降低。
Isolated defects of ether lipid (EL) biosynthesis in humans cause rhizomelic chondrodysplasia punctata type 2 and type 3, serious peroxisomal disorders. Using a previously described mouse model [Rodemer, C., Thai, T.P., Brugger, B., Kaercher, T., Werner, H., Nave, K.A., Wieland, F., Gorgas, K., and Just, W.W. (2003) Inactivation of ether lipid biosynthesis causes male infertility, defects in eye development and optic nerve hypoplasia in mice. Hum. Mol. Genet., 12, 1881–1895], we investigated the effect of EL deficiency in isolated murine nerve terminals (synaptosomes) on the pre-synaptic release of the neurotransmitters (NTs) glutamate and acetylcholine. Both Ca2+-dependent exocytosis and Ca2+-independent efflux of the transmitters were affected. EL-deficient synaptosomes respire at a reduced rate and exhibit a lowered adenosin-5′-triphosphate/adenosine diphosphate (ATP/ADP) ratio. Consequently, ATP-driven processes, such as synaptic vesicle cycling and maintenance of Na+, K+ and Ca2+ homeostasis, might be disturbed. Analyzing reactive oxygen species in EL-deficient neural and non-neural tissues revealed that plasmalogens (PLs), the most abundant EL species in mammalian central nervous system, considerably contribute to the generation of the lipid peroxidation product malondialdehyde. Although EL-deficient tissue contains less lipid peroxidation products, fibroblasts lacking ELs are more susceptible to induced oxidative stress. In summary, these results suggest that due to the reduced energy state of EL-deficient tissue, the Ca2+-independent efflux of NTs increases while the Ca2+-dependent release declines. Furthermore, lack of PLs is mainly compensated for by an increase in the concentration of phosphatidylethanolamine and results in a significantly lowered level of lipid peroxidation products in the brain cortex and cerebellum.