The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA.
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
Mol Cell Biol. 2018 Sep 28;38(20). doi: 10.1128/MCB.00011-18. Print 2018 Oct 15.
In a whole-exome sequencing study of multiplex Alzheimer's disease (AD) families, we investigated three neuronal ceroid lipofuscinosis genes that have been linked to retromer, an intracellular trafficking pathway associated with AD: ceroid lipofuscinosis 3 (CLN3), ceroid lipofuscinosis 5 (CLN5), and cathepsin D (CTSD). We identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD. We find that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5's normal cellular location. The AD-associated CLN5 variant is shown here to reduce the normal processing of cathepsin D and to decrease levels of full-length amyloid precursor protein (APP), suggestive of a defect in retromer-dependent trafficking.
在一项针对多症阿尔茨海默病（AD）家族的全外显子组测序研究中，我们研究了三个与内体蛋白分选转运复合体（retromer）相关的神经细胞蜡样脂褐质沉积症基因，该复合体与 AD 有关：神经细胞蜡样脂褐质沉积症 3（CLN3）、神经细胞蜡样脂褐质沉积症 5（CLN5）和组织蛋白酶 D（CTSD）。我们在 CLN5 基因中发现了一个错义变异 c.A959G（p.Asn320Ser），该变异与 AD 共分离。我们发现，这种变异会导致表达蛋白的糖基化缺陷，从而使其在内质网中滞留，减少递送至溶酶体腔的数量，而溶酶体腔是 CLN5 的正常细胞位置。这里显示，与 AD 相关的 CLN5 变异会减少组织蛋白酶 D 的正常加工，并降低全长淀粉样前体蛋白（APP）的水平，提示 retromer 依赖性运输存在缺陷。
