中文摘要：

泡沫巨噬細胞的積累是脫髓鞘腦疾病的病理特征。代謝紊亂和細胞內脂質的外排是這些疾病中有害的泡沫巨噬細胞表型發展的根本原因，但其背后的分子機制尚不明確。在這里，我們展示了泛素-蛋白酶體系統控制大腦中脂質負荷巨噬細胞的膽固醇外排轉運蛋白ATP結合盒A1（ABCA1）的周轉。我們報告說，髓鞘衍生脂質的積累促進了巨噬細胞中泛素-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。這增加了細胞脂質的積累并誘導了損害再髓鞘化的炎性巨噬細胞表型。我們進一步確定參與Tat的蛋白30（TIP30），作為介導進口蛋白β的核內導入的抑制劑，是細胞質UBE3A水平的一個重要調節因子。總之，我們的發現將UBE3A確定為泡沫細胞形成的驅動因素，并表明靶向UBE3A介導的ABCA1降解是增強中樞神經系統修復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

產品信息：

貨號：CP-005-005

規格：5ml+5ml

品牌：Liposoma

產地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes

辦事處：Target Technology(靶點科技)

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

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

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.

腦切片體外巨噬細胞清除材料和方法文獻截圖：