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颗粒蛋白前体缺乏导致葡萄糖脑苷脂酶活性降低。

Progranulin deficiency leads to reduced glucocerebrosidase activity.

机构信息

Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, United States of America.

School of Chemistry and Biochemistry, Georgia Institute of Technology, NW, Atlanta, GA, United States of America.

出版信息

PLoS One. 2019 Jul 10;14(7):e0212382. doi: 10.1371/journal.pone.0212382. eCollection 2019.

DOI:10.1371/journal.pone.0212382
PMID:31291241
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6619604/
Abstract

Mutation in the GRN gene, encoding the progranulin (PGRN) protein, shows a dose-dependent disease correlation, wherein haploinsufficiency results in frontotemporal lobar degeneration (FTLD) and complete loss results in neuronal ceroid lipofuscinosis (NCL). Although the exact function of PGRN is unknown, it has been increasingly implicated in lysosomal physiology. Here we report that PGRN interacts with the lysosomal enzyme, glucocerebrosidase (GCase), and is essential for proper GCase activity. GCase activity is significantly reduced in tissue lysates from PGRN-deficient mice. This is further evidence that reduced lysosomal hydrolase activity may be a pathological mechanism in cases of GRN-related FTLD and NCL.

摘要

GRN 基因（编码颗粒体蛋白）突变与疾病呈剂量相关性，杂合子缺失导致额颞叶痴呆（FTLD），完全缺失导致神经元蜡样脂褐质沉积症（NCL）。尽管 PGRN 的确切功能尚不清楚，但它越来越多地与溶酶体生理学有关。在这里，我们报告 PGRN 与溶酶体酶葡萄糖脑苷脂酶（GCase）相互作用，是 GCase 活性所必需的。PGRN 缺乏的小鼠组织裂解物中的 GCase 活性显著降低。这进一步证明了溶酶体水解酶活性降低可能是 GRN 相关 FTLD 和 NCL 的病理机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/b3345c08b73b/pone.0212382.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/decab73f9114/pone.0212382.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/84c2393e9c4d/pone.0212382.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/46dba8e9e0ac/pone.0212382.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/7a8061235191/pone.0212382.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/eeca1f3ef5db/pone.0212382.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/b3345c08b73b/pone.0212382.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/decab73f9114/pone.0212382.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/84c2393e9c4d/pone.0212382.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/46dba8e9e0ac/pone.0212382.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/7a8061235191/pone.0212382.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/eeca1f3ef5db/pone.0212382.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7108/6619604/b3345c08b73b/pone.0212382.g006.jpg

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本文引用的文献

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2
The role of glucocerebrosidase in Parkinson disease pathogenesis.葡萄糖脑苷脂酶在帕金森病发病机制中的作用。
FEBS J. 2018 Oct;285(19):3591-3603. doi: 10.1111/febs.14393. Epub 2018 Feb 19.
3
Progranulin-mediated deficiency of cathepsin D results in FTD and NCL-like phenotypes in neurons derived from FTD patients.颗粒蛋白前体缺失导致组织蛋白酶 D 引起的额颞叶痴呆和神经细胞蜡样质脂褐质沉积症样表型，来源于额颞叶痴呆患者的神经元。
与原颗粒蛋白缺乏和额颞叶痴呆相关的鞘磷脂酶活性降低。
Neurobiol Dis. 2025 Sep;213:107024. doi: 10.1016/j.nbd.2025.107024. Epub 2025 Jul 7.
4
Progranulin's Protective Mechanisms and Therapeutic Potential in Cardiovascular Disease.颗粒蛋白前体在心血管疾病中的保护机制及治疗潜力
Cells. 2025 May 22;14(11):762. doi: 10.3390/cells14110762.
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PGRN as an emerging regulator of lipid metabolism in neurodegenerative diseases.原纤维蛋白聚糖作为神经退行性疾病中脂质代谢的新兴调节因子。
Commun Biol. 2025 Jun 2;8(1):844. doi: 10.1038/s42003-025-08272-9.
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ASO-mediated knock-down of GPNMB in mutant-GRN and in Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses.在突变型GRN和Grn缺陷的外周髓样细胞中，ASO介导的GPNMB敲低会破坏溶酶体功能和免疫反应。
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7
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8
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9
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10
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