Wang Jun, Yu Jin-Tai, Tan Lan
Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.
Mol Neurobiol. 2015 Apr;51(2):480-6. doi: 10.1007/s12035-014-8779-5. Epub 2014 Jun 17.
Rare coding variants in the phospholipase D3 (PLD3) gene, also known as HU-K4, have recently been identified to increase the risk for late-onset Alzheimer's disease (LOAD) by the whole exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large independent LOAD case-control data series. PLD3 is highly expressed in the brain, especially mainly in neurons, but at a lower level in almost all tissues. The level of PLD3 was found to be downregulated in Alzheimer's disease (AD) brains, which was negatively correlated with amyloid precursor protein (APP) and amyloid-β (Aβ) levels. These findings suggested that PLD3 might be involved in AD pathogenesis through APP processing. Here, we briefly summarize the biochemical properties of PLD3, review recent genetic and expression findings of PLD3 that related to AD, and also speculate on the possible roles of PLD3 in the progression of this disease. Based on the contributing effects of PLD3 in AD pathogenesis, targeting PLD3 may provide new opportunities for AD therapeutic strategies.
磷脂酶D3（PLD3）基因，也称为HU-K4，其罕见的编码变异最近通过对14个大型晚发性阿尔茨海默病（LOAD）家系进行全外显子组测序（WES）以及在几个大型独立LOAD病例对照数据系列中对候选变异进行后续分析，被确定会增加患LOAD的风险。PLD3在大脑中高度表达，尤其是主要在神经元中，但在几乎所有组织中的表达水平较低。研究发现，PLD3在阿尔茨海默病（AD）大脑中的表达下调，这与淀粉样前体蛋白（APP）和淀粉样β蛋白（Aβ）水平呈负相关。这些发现表明，PLD3可能通过APP加工参与AD发病机制。在此，我们简要总结PLD3的生化特性，回顾与AD相关的PLD3的最新遗传学和表达研究结果，并推测PLD3在该疾病进展中的可能作用。基于PLD3在AD发病机制中的作用，靶向PLD3可能为AD治疗策略提供新的机会。
