中文摘要：

泡沫巨噬細(xì)胞的積累是脫髓鞘腦疾病的病理特征。代謝紊亂和細(xì)胞內(nèi)脂質(zhì)的外排是這些疾病中有害的泡沫巨噬細(xì)胞表型發(fā)展的根本原因，但其背后的分子機(jī)制尚不明確。在這里，我們展示了泛素-蛋白酶體系統(tǒng)控制大腦中脂質(zhì)負(fù)荷巨噬細(xì)胞的膽固醇外排轉(zhuǎn)運(yùn)蛋白ATP結(jié)合盒A1（ABCA1）的周轉(zhuǎn)。我們報告說，髓鞘衍生脂質(zhì)的積累促進(jìn)了巨噬細(xì)胞中泛素-蛋白E3連接酶A（UBE3A）的豐度和活性，這刺激了ABCA1的泛素化及隨后的降解。這增加了細(xì)胞脂質(zhì)的積累并誘導(dǎo)了損害再髓鞘化的炎性巨噬細(xì)胞表型。我們進(jìn)一步確定參與Tat的蛋白30（TIP30），作為介導(dǎo)進(jìn)口蛋白β的核內(nèi)導(dǎo)入的抑制劑，是細(xì)胞質(zhì)UBE3A水平的一個重要調(diào)節(jié)因子。總之，我們的發(fā)現(xiàn)將UBE3A確定為泡沫細(xì)胞形成的驅(qū)動因素，并表明靶向UBE3A介導(dǎo)的ABCA1降解是增強(qiáng)中樞神經(jīng)系統(tǒng)修復(fù)的一個有前景的策略。

英文摘要：

The accumulation of foamy macrophages is a pathological hallmark of demyelinating brain disorders. Perturbed metabolism and efflux of intracellular lipids underlie the development of a harmful foamy macrophage phenotype in these disorders, yet, the molecular mechanisms underlying this dysregulation are poorly understood. Here, we show that the ubiquitin-proteasome system controls the turnover of the cholesterol efflux transporter ATP-binding cassette A1 (ABCA1) in lipid-loaded macrophages in the brain. We report that accumulation of myelin-derived lipids promotes the abundance and activity of ubiquitin-protein E3 ligase A (UBE3A) in macrophages, which stimulates ABCA1 ubiquitination and subsequent degradation. This boosts cellular lipid accumulation and induces an inflammatory macrophage phenotype that impairs remyelination. We further establish Tat-interacting protein 30 (TIP30), an inhibitor of importin β-mediated nuclear import, as an essential regulator of cytosolic UBE3A levels. Together, our findings identify UBE3A as a driver of foam cell formation and indicate that targeting UBE3A-mediated ABCA1 degradation is a promising strategy to enhance central nervous system repair.

論文信息：

論文題目：UBE3A promotes foam cell formation and counters remyelination by targeting ABCA1 for proteasomal degradation

期刊名稱：Nature Communications

時間期卷：16, Article number: 8077 (2025)

在線時間：2025年8月29日

DOI：doi.org/10.1038/s41467-025-62053-w

產(chǎn)品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology(靶點(diǎn)科技)

Clodronate Liposomes氯膦酸鹽脂質(zhì)體清除泡沫巨噬細(xì)胞，泡沫巨噬細(xì)胞含有過量的細(xì)胞內(nèi)來源于髓鞘的脂質(zhì)，導(dǎo)致多發(fā)性硬化癥（MS）等神經(jīng)退行性疾病的病理。雖然對富含脂質(zhì)的結(jié)構(gòu)，如改良的脂蛋白和髓鞘的攝取，將巨噬細(xì)胞表型重塑為通常與組織修復(fù)和免疫抑制相關(guān)的表型，但這種解決疾病的表型僅是短暫的。我們和其他研究者發(fā)現(xiàn)，巨噬細(xì)胞中髓鞘來源脂質(zhì)的過度積累，尤其在衰老過程中，使泡沫細(xì)胞傾向于更具炎癥性和促進(jìn)疾病的表型。這種有害表型的誘導(dǎo)與大腦修復(fù)模型中損傷恢復(fù)受損密切相關(guān)。從機(jī)制上講，細(xì)胞內(nèi)脂質(zhì)的新陳代謝失調(diào)，主要由于膽固醇外流減少，導(dǎo)致細(xì)胞脂質(zhì)含量失衡和有害泡沫巨噬細(xì)胞亞群的發(fā)展。荷蘭Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于Nature Communications：氯膦酸鹽脂質(zhì)體clodronateliposomes體外清除腦切片Cerebellar brain slices 巨噬細(xì)胞。

Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體體外清除腦切片巨噬細(xì)胞的材料和方法：

Brain slice cultures

Cerebellar slices were obtained from male and female wild-type and Ube3a?/? P9-P11 mouse pups as described previously8,66. Briefly, cerebellar parasagittal slices (300-µm thick) were cut on a MacIlwain tissue chopper and transferred onto membranes of 30-mm Millipore culture inserts with a 0.4-μm pore size (Millicell; Millipore). Slices were maintained in culture on top of the membranes in six-well plates containing 1?ml of medium [MEM (Thermo Fisher Scientific, 32360-026) supplemented with 25% horse serum (Life Technologies, S-HS-EU-015), 25% Hanks’ balanced salt solution (Invitrogen, 14025092), 1% P/S, 1% Glutamax (Sigma, 35050-038), 1.3% glucose (Sigma, G8644), and 1.1% 1?M HEPES (Thermo Fisher Scientific, 15630-080) at 37?°C, 5% CO2. For phagocyte depletion, slices were treated with clodronate or empty liposomes (0.5?mg/ml, LIPOSOMA) immediately after isolation for 24?h. Slices were repleted with 4?×?103 LPS- (100?ng/µl, Sigma, 437627, 18?h) or IL4-stimulated (20?ng/µL, Peprotech, 214-14, 18?h) wild-type or Ube3a?/? BMDMs by adding them directly to the slice in a 1.5?µl drop, without touching the slice. Slices were left to recover for 2 days, after which demyelination was induced by treating the slices with lysolecithin (0.5?mg/ml, Sigma, 62963) for 16?h. Afterward, slices were washed and kept in culture for 6 days, followed by histological and biochemical analysis.

腦切片體外巨噬細(xì)胞清除材料和方法文獻(xiàn)截圖：