CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.
CLN3 is required for the clearance of glycerophosphodiesters from lysosomes.
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DOI：
10.1038/s41586-022-05221-y
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发表时间：
2022-09
期刊：
影响因子：
64.8
通讯作者：
Abu-Remaileh M
中科院分区：
文献类型：
--
作者：
Laqtom NN;Dong W;Medoh UN;Cangelosi AL;Dharamdasani V;Chan SH;Kunchok T;Lewis CA;Heinze I;Tang R;Grimm C;Dang Do AN;Porter FD;Ori A;Sabatini DM;Abu-Remaileh M
溶酶体有许多作用，包括降解大分子和向细胞核发送信号。溶酶体功能障碍发生在各种人类病症中，例如常见的神经退行性疾病和单基因溶酶体贮积症（LSD）。对于大多数LSD的致病基因已经确定，但在一些涉及的基因的功能是未知的，部分原因是溶酶体占据细胞体积的一小部分，使溶酶体内容物的变化是难以检测。在这里，我们开发的LysoTag小鼠的组织特异性分离的完整的溶酶体，是兼容的多模式分析其内容。我们将其应用于CLN3的研究，CLN3是一种功能不清楚的溶酶体跨膜蛋白，其丢失会导致青少年神经元蜡样脂褐质沉积症（Batten病），一种致命的神经退行性LSD。来自缺乏CLN3的小鼠的脑的溶酶体的非靶向代谢物分析揭示了甘油磷酸二酯（GPD）（甘油磷脂酶的终产物）的大量积累。GPD也在CLN3缺陷培养细胞的溶酶体中积累，并且我们表明CLN3是其溶酶体排出所需的。CLN3的缺失也破坏了溶酶体中的甘油磷脂酶。最后，我们发现Batten病患者的脑脊液中甘油磷酸肌醇水平升高，表明其作为疾病生物标志物的潜在用途。我们的研究结果表明，CLN3是必需的溶酶体清除GPD和揭示巴滕病作为一种神经退行性LSD与甘油磷脂代谢缺陷。
Lysosomes have many roles, including degrading macromolecules and signaling to the nucleus. Lysosomal dysfunction occurs in various human conditions, such as common neurodegenerative diseases and monogenic lysosomal storage disorders (LSDs). 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 apply it to the study of CLN3, a lysosomal transmembrane protein of unclear function whose loss 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 Batten disease patients, suggesting their potential use 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.
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影响因子：
7.4
作者：
Bird, Susan S.;Marur, Vasant R.;Sniatynski, Matthew J.;Greenberg, Heather K.;Kristal, Bruce S.
通讯作者：
Kristal, Bruce S.
影响因子：
14.9
作者：
Allen F;Pon A;Wilson M;Greiner R;Wishart D
通讯作者：
Wishart D
影响因子：
3.5
作者：
Järvelä, I;Sainio, M;Jalanko, A
通讯作者：
Jalanko, A
影响因子：
4.3
作者：
Padilla-Lopez, Sergio;Langager, Deanna;Pearce, David A.
通讯作者：
Pearce, David A.
DOI：
10.1038/s41436-020-01035-3
发表时间：
2021-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Dang Do AN;Sinaii N;Masvekar RR;Baker EH;Thurm AE;Soldatos AG;Bianconi SE;Bielekova B;Porter FD
通讯作者：
Porter FD