Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease.
Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease.
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DOI：
10.1016/j.ebiom.2023.104628
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发表时间：
2023-06
期刊：
影响因子：
11.1
通讯作者：
Marquer, Catherine
中科院分区：
文献类型：
--
作者：
Chen, Jacinda;Soni, Rajesh Kumar;Xu, Yimeng;Simoes, Sabrina;Liang, Feng-Xia;DeFreitas, Laura;Hwang Jr, Robert;Montesinos, Jorge;Lee, Joseph H.;Area-Gomez, Estela;Nandakumar, Renu;Vardarajan, Badri;Marquer, Catherine
关键词：
神经元蜡样质脂褐质沉积症（NCL）最常见的形式是青少年CLN 3病（JNCL），这是一种目前无法治愈的神经退行性疾病，由CLN 3基因突变引起。基于我们以前的工作和CLN 3影响阳离子非依赖性甘露糖-6磷酸受体及其配体NPC 2的运输的前提下，我们假设CLN 3的功能障碍导致JNCL患者脑中晚期内体/溶酶体（LE/Lys）中胆固醇的异常积累。使用免疫纯化策略从冷冻尸检脑样品中分离完整的LE/Lys。将从JNCL患者的样品中分离的LE/Lys与年龄匹配的未受影响的对照和尼曼-匹克C型（NPC）疾病患者进行比较。事实上，NPC 1或NPC 2中的突变导致NPC疾病样品的LE/Lys中胆固醇的积累，从而提供阳性对照。然后分别使用脂质组学和蛋白质组学分析LE/Lys的脂质和蛋白质含量。与对照组相比，从JNCL患者中分离的LE/Lys的脂质和蛋白质谱发生了深刻的改变。重要的是，胆固醇在JNCL样品的LE/Lys中积累的程度与NPC样品相当。LE/Lys的血脂谱在JNCL和NPC患者中相似，除了双（单酰基甘油）磷酸盐（BMP）水平。在JNCL和NPC患者的LE/Lys中检测到的蛋白质谱除了NPC 1的水平之外似乎是相同的。我们的研究结果支持JNCL是一种溶酶体胆固醇储存障碍。我们的研究结果还支持JNCL和NPC疾病共享致病途径，导致脂质和蛋白质的异常溶酶体积累，因此表明NPC疾病的治疗可能对JNCL患者有益。这项工作为JNCL模型系统的进一步机制研究和这种疾病的可能治疗干预开辟了新的途径。.
The most common form of neuronal ceroid lipofuscinosis (NCL) is juvenile CLN3 disease (JNCL), a currently incurable neurodegenerative disorder caused by mutations in the CLN3 gene. Based on our previous work and on the premise that CLN3 affects the trafficking of the cation-independent mannose-6 phosphate receptor and its ligand NPC2, we hypothesised that dysfunction of CLN3 leads to the aberrant accumulation of cholesterol in the late endosomes/lysosomes (LE/Lys) of JNCL patients’ brains. An immunopurification strategy was used to isolate intact LE/Lys from frozen autopsy brain samples. LE/Lys isolated from samples of JNCL patients were compared with age-matched unaffected controls and Niemann–Pick Type C (NPC) disease patients. Indeed, mutations in NPC1 or NPC2 result in the accumulation of cholesterol in LE/Lys of NPC disease samples, thus providing a positive control. The lipid and protein content of LE/Lys was then analysed using lipidomics and proteomics, respectively. Lipid and protein profiles of LE/Lys isolated from JNCL patients were profoundly altered compared to controls. Importantly, cholesterol accumulated in LE/Lys of JNCL samples to a comparable extent than in NPC samples. Lipid profiles of LE/Lys were similar in JNCL and NPC patients, except for levels of bis(monoacylglycero)phosphate (BMP). Protein profiles detected in LE/Lys of JNCL and NPC patients appeared identical, except for levels of NPC1. Our results support that JNCL is a lysosomal cholesterol storage disorder. Our findings also support that JNCL and NPC disease share pathogenic pathways leading to aberrant lysosomal accumulation of lipids and proteins, and thus suggest that the treatments available for NPC disease may be beneficial to JNCL patients. This work opens new avenues for further mechanistic studies in model systems of JNCL and possible therapeutic interventions for this disorder. .
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影响因子：
4.6
作者：
Area-Gomez E;Larrea D;Yun T;Xu Y;Hupf J;Zandkarimi F;Chan RB;Mitsumoto H
通讯作者：
Mitsumoto H
DOI：
10.1093/bioinformatics/btx752
发表时间：
2018-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
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影响因子：
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作者：
Ahrens-Nicklas, Rebecca C.;Tecedor, Luis;Marsh, Eric D.
通讯作者：
Marsh, Eric D.
影响因子：
3.7
作者：
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通讯作者：
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