Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, UK.
Euan MacDonald Centre for Motor Neurone Disease Research and Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9JZ, UK.
J Comp Neurol. 2018 Sep 1;526(13):1995-2009. doi: 10.1002/cne.24466. Epub 2018 Aug 2.
Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function, and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl-transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction (NMJ) revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although NMJ length is normal in lace mutants, the number of boutons per NMJ is reduced to ∼50% of the wild type number. Synaptic boutons in lace mutants are much larger but show little perturbation to the general ultrastructure. Electrophysiological analysis of lace mutant synapses revealed strong synaptic transmission coupled with predominance of depression over facilitation. The structural and functional phenotypes of lace mirrored aspects of Basigin (Bsg), a small Ig-domain adhesion molecule also known to regulate synaptic structure and function. Mutant combinations of lace and Bsg generated large synaptic boutons, while lace mutants showed abnormal accumulation of Bsg at synapses, suggesting that Bsg requires sphingolipid to regulate structure of the synapse. In support of this, we found Bsg to be enriched in lipid rafts. Our data points to a role for sphingolipids in the regulation and fine-tuning of synaptic structure and function while sphingolipid regulation of synaptic structure may be mediated via the activity of Bsg.
鞘脂大量存在于突触中，其在调节突触结构、功能和退化方面发挥作用。然而，它们在这些过程中的具体作用仍不清楚。丝氨酸棕榈酰转移酶（SPT）是鞘脂合成的第一步酶。对果蝇幼虫神经肌肉接头（NMJ）的分析显示，SPT 酶亚基 lace/SPTLC2 的突变导致突触结构和功能缺陷。尽管 lace 突变体中的 NMJ 长度正常，但每个 NMJ 的突触点数量减少到野生型的约 50%。lace 突变体中的突触突触点大得多，但对一般超微结构几乎没有干扰。lace 突变体突触的电生理分析显示，突触传递强烈，易化作用占主导地位。lace 的结构和功能表型反映了 Basigin（Bsg）的某些方面，Bsg 是一种小的 Ig 结构域粘附分子，也被认为可以调节突触结构和功能。lace 和 Bsg 的突变组合产生了大的突触突触点，而 lace 突变体显示 Bsg 在突触处异常积累，表明 Bsg 需要鞘脂来调节突触结构。支持这一点的是，我们发现 Bsg 在脂筏中富集。我们的数据表明，鞘脂在调节突触结构和功能方面起着重要作用，而鞘脂对突触结构的调节可能是通过 Bsg 的活性介导的。
