小柯机器人

美国斯坦福大学Monther Abu-Remaileh小组发现，CLN3是清除溶酶体中的甘油磷酸二酯所需。这一研究成果于2022年9月21日在线发表在国际学术期刊《自然》上。

研究人员开发了LysoTag小鼠，用于组织特异性分离完整的溶酶体，并与多模式分析其内容相兼容。研究人员使用LysoTag小鼠来研究CLN3，一种功能未知的溶酶体跨膜蛋白。在儿童中，CLN3的缺失会导致青少年神经元类脂褐素病（Batten病），这是一种致命的神经退行性溶酶体储存障碍（LSD）。缺乏CLN3的小鼠大脑溶酶体的非靶向代谢物分析显示，甘油磷酸二酯（GPD）的大量积累，即甘油磷酸脂分解的最终产物。GPD也积聚在CLN3缺陷的培养细胞的溶酶体中，结果表明CLN3是其溶酶体排出所需的。CLN3的丧失也破坏了溶酶体中的甘油磷脂分解作用。最后，研究人员发现巴顿病患者脑脊液中的甘油磷酸肌醇水平升高，表明甘油磷酸肌醇可能被用作疾病的生物标志物。这些研究结果表明，CLN3是溶酶体清除GPD所需的，并揭示了巴顿病是一种具有甘油磷脂代谢缺陷的神经退行性LSD。

据介绍，溶酶体有许多作用，包括降解大分子和向细胞核发出信号。溶酶体功能障碍发生在各种人类疾病中，如常见的神经退行性疾病和单基因LSD。对于大多数LSD来说，致病基因已经被确定，但在某些情况下，相关基因的功能是未知的，部分原因是溶酶体只占细胞体积的一小部分，因此溶酶体内容物的变化很难被发现。

附：英文原文

Title: CLN3 is required for the clearance of glycerophosphodiesters from lysosomes

Author: Laqtom, Nouf N., Dong, Wentao, Medoh, Uche N., Cangelosi, Andrew L., Dharamdasani, Vimisha, Chan, Sze Ham, Kunchok, Tenzin, Lewis, Caroline A., Heinze, Ivonne, Tang, Rachel, Grimm, Christian, Dang Do, An N., Porter, Forbes D., Ori, Alessandro, Sabatini, David M., Abu-Remaileh, Monther

Issue&Volume: 2022-09-21

Abstract: Lysosomes have many roles, including degrading macromolecules and signalling to the nucleus1. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs)2,3,4. For most LSDs, the causal genes have been identified but, in some, the function of the implicated gene is unknown, in part because lysosomes occupy a small fraction of the cellular volume so that changes in lysosomal contents are difficult to detect. Here we develop the LysoTag mouse for the tissue-specific isolation of intact lysosomes that are compatible with the multimodal profiling of their contents. We used the LysoTag mouse to study CLN3, a lysosomal transmembrane protein with an unknown function. In children, the loss of CLN3 causes juvenile neuronal ceroid lipofuscinosis (Batten disease), a lethal neurodegenerative LSD. Untargeted metabolite profiling of lysosomes from the brains of mice lacking CLN3 revealed a massive accumulation of glycerophosphodiesters (GPDs)—the end products of glycerophospholipid catabolism. GPDs also accumulate in the lysosomes of CLN3-deficient cultured cells and we show that CLN3 is required for their lysosomal egress. Loss of CLN3 also disrupts glycerophospholipid catabolism in the lysosome. Finally, we found elevated levels of glycerophosphoinositol in the cerebrospinal fluid of patients with Batten disease, suggesting the potential use of glycerophosphoinositol as a disease biomarker. Our results show that CLN3 is required for the lysosomal clearance of GPDs and reveal Batten disease as a neurodegenerative LSD with a defect in glycerophospholipid metabolism.

DOI: 10.1038/s41586-022-05221-y

Source: https://www.nature.com/articles/s41586-022-05221-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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