mGluR5 细胞内活性增强导致尼曼皮克 C 型病的精神改变。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-23 DOI:10.1038/s41419-024-07158-8
Ana Toledano-Zaragoza, Violeta Enriquez-Zarralanga, Sara Naya-Forcano, Víctor Briz, Rocío Alfaro-Ruíz, Miguel Parra-Martínez, Daniel N Mitroi, Rafael Luján, José A Esteban, María Dolores Ledesma
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引用次数: 0

摘要

尼曼-皮克病 C 型(NPC)是由胆固醇转运蛋白 NPC1 突变引起的,导致脂质在溶酶体内积聚和精神改变。我们利用一种 NPC 小鼠模型(Npc1nmf164)显示,在 NPC1 缺失的神经元中,mGluR5 溶酶体积累异常,质膜减少。这种表型是通过遗传和药物 NPC1 沉默诱导野生型(wt)神经元形成的。提取胆固醇可使 mGluR5 在 NPC1 缺失神经元中的分布正常化。在非膜渗透性或膜渗透性 mGluR5 激动剂的刺激下,Npc1nmf164 海马切片的 mGluR-LTD 分别低于或高于 wt 海马切片。口服 mGluR5 拮抗剂 2-氯-4-((2,5-二甲基-1-(4-(三氟甲氧基)苯基)-1H-咪唑-4-基)乙炔基)吡啶(CTEP)可减少 mGluR-LTD 并改善 Npc1nmf164 小鼠的精神异常。在一名鼻咽癌患者体内发现了神经元 mGluR5 水平的升高。这些结果表明,mGluR5的改变与鼻咽癌精神状况有关,并提供了一种新的治疗策略,或许能帮助这种毁灭性疾病的患者。
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Enhanced mGluR5 intracellular activity causes psychiatric alterations in Niemann Pick type C disease.

Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1nmf164) we show aberrant mGluR5 lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR5 distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR5 was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1nmf164 hippocampal slices. mGluR-LTD was lower or higher in Npc1nmf164 slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR5 agonists, respectively. Oral treatment with the mGluR5 antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1nmf164 mice. Increased neuronal mGluR5 levels were found in an NPC patient. These results implicate mGluR5 alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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