Sinbaglustat ameliorates disease pathology in a murine model of GM1 gangliosidosis without affecting CNS ganglioside levels

辛巴格司他在GM1神经节苷脂贮积症小鼠模型中改善疾病病理，且不影响中枢神经系统神经节苷脂水平

Sinbaglustat is a brain-penetrating small molecule that inhibits the non-lysosomal glucocerebrosidase (GBA2) and, with lower potency, glucosylceramide synthase (GCS). Sinbaglustat has passed clinical phase I. Our preclinical study assessed its efficacy in a transgenic mouse model of GM1 gangliosidosis, lacking a functional β-galactosidase enzyme (Glb1-/-). Starting at 4 weeks of age, mice were either treated with a nominal dose of 10 or 300 mg/kg/day of sinbaglustat or remained untreated. Wild-type (WT) mice served as control. Body weight, clinical and neurological signs, and motor function was assessed until 17-18 weeks (4 months) and 30 weeks (7 months) of age when mice were euthanized for ex vivo assessments. In comparison to WT, Glb1-/- mice showed the expected accumulation of GM1 gangliosidosis-related sphingolipids, neuropathology, and behavioral deficits. Both dosages of sinbaglustat left GM1 and lyso GM1 levels in the brain unaffected but delayed the onset of motor impairment and progression of clinical disease in Glb1-/- mice with the higher dose being more efficacious. Histologically and immunohistochemically, both treatment groups of Glb1-/- mice displayed reduced neuronal vacuolation. Only the higher dose of sinbaglustat decreased axonal damage and astrogliosis, which was also associated with a decrease of the axonal/neuronal damage marker plasma neurofilament light at 4 months (17-18 weeks). Both doses of sinbaglustat increased the GBA2 substrate glucosylceramide (GluCer) in the brain, while only the high dose reduced GluCer and other glycosphingolipids (GSLs) in the periphery indicating additional inhibition of GCS. We conclude that sinbaglustat had a therapeutic-like effect in the GM1 gangliosidosis mouse model.

辛巴格鲁司他是一种可穿透血脑屏障的小分子，它能抑制非溶酶体性葡萄糖脑苷脂酶（GBA2），对葡萄糖神经酰胺合酶（GCS）也有较弱的抑制作用。辛巴格鲁司他已通过了I期临床试验。我们的临床前研究评估了其在GM1神经节苷脂贮积症转基因小鼠模型（缺乏功能性β - 半乳糖苷酶（Glb1 - / - ））中的疗效。从4周龄开始，小鼠分别接受标称剂量为10或300 mg/kg/天的辛巴格鲁司他治疗，或不接受治疗。野生型（WT）小鼠作为对照。对小鼠的体重、临床和神经症状以及运动功能进行评估，直至17 - 18周龄（4个月）和30周龄（7个月），届时对小鼠实施安乐死以进行离体评估。与野生型小鼠相比，Glb1 - / - 小鼠出现了预期的GM1神经节苷脂贮积症相关鞘脂蓄积、神经病理学改变和行为缺陷。两个剂量的辛巴格鲁司他均未影响大脑中GM1和溶血型GM1的水平，但延缓了Glb1 - / - 小鼠运动障碍的发生和临床疾病的进展，高剂量的效果更显著。从组织学和免疫组织化学角度来看，两个治疗组的Glb1 - / - 小鼠神经元空泡化均有所减轻。只有高剂量的辛巴格鲁司他减轻了轴突损伤和星形胶质细胞增生，这也与4个月龄（17 - 18周）时血浆神经丝轻链（轴突/神经元损伤标志物）水平降低有关。两个剂量的辛巴格鲁司他均使大脑中GBA2底物葡萄糖神经酰胺（GluCer）水平升高，而只有高剂量降低了外周组织中的GluCer和其他糖鞘脂（GSLs）水平，表明其对GCS有额外的抑制作用。我们得出结论，辛巴格鲁司他在GM1神经节苷脂贮积症小鼠模型中具有类似治疗的效果。

REF: Wannemacher R, Jubran-Rudolf L, Zdora I, et al. Sinbaglustat ameliorates disease pathology in a murine model of GM1 gangliosidosis without affecting CNS ganglioside levels. Neurobiol Dis. 2025;210:106917. doi:10.1016/j.nbd.2025.106917 PMID: 40250720

Early plasma ceramide and sphingomyelin levels reflect APOE genotype but not familial Alzheimer's disease gene mutations in female 5xFAD mice, with brain-region specific sphingolipid alterations

早期血浆神经酰胺和鞘磷脂水平反映了雌性 5xFAD 小鼠的载脂蛋白 E（APOE）基因型，但不反映家族性阿尔茨海默病基因突变情况，且存在脑区特异性鞘脂改变

Pathophysiological changes associated with Alzheimer's disease (AD) begin decades before dementia onset, with age and APOE ε4 genotype as major risk factors [1-4]. Primary risk factors for developing AD include aging and number of copies of the apolipoprotein E (APOE) ε4 allele. Altered sphingolipid metabolism is increasingly implicated in early AD. However, the relationship between early plasma and brain sphingolipid changes-particularly in the context of APOE genotype-remains poorly defined. In this study, we analyzed plasma and brain sphingolipid profiles in transgenic AD mice carrying human APOE3 or APOE4 variants, with or without familial AD mutations (E3FAD and E4FAD). Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we assessed 110 sphingolipid species across four major classes (ceramides (Cers), hexosylceramides (HexCers), lactosylceramides (LacCers), and sphingomyelins (SMs)) at 2, 4, and 6 months in plasma and at 6 months in brain tissue in the cortex, hippocampus, striatum, and cerebellum. Our results demonstrate that early plasma sphingolipid alterations are largely driven by APOE genotype rather than AD pathology. Specifically, APOE4 carriers showed significant increases in SM species and reductions in Cer species compared to APOE3 carriers, independent of age or AD genotype. Brain lipid profiles showed minimal changes across genotypes after region correction. However, combined p-value analyses revealed APOE- and EFAD-dependent differences in the composition of primarily cortical sphingolipids. ROC analyses demonstrated high discriminative power of plasma sphingolipids for APOE, but not for AD genotype. These findings suggest that early plasma lipid profiles in female 5xFAD mice are more strongly influenced by APOE genotype than by overt AD pathology, potentially reflecting systemic pathways linked to APOE4-associated AD risk, while early disease-associated changes in the brain appear to be subtle and region-specific. These results underscore the importance of accounting for APOE genotype in early-stage AD lipidomic studies and in the interpretation of peripheral lipid biomarkers.

与阿尔茨海默病（AD）相关的病理生理变化在痴呆症发作前数十年就已开始，年龄和载脂蛋白E（APOE）ε4基因型是主要危险因素[1 - 4]。患AD的主要危险因素包括衰老和载脂蛋白E（APOE）ε4等位基因的拷贝数。鞘脂代谢改变在早期AD中的作用日益受到关注。然而，早期血浆和大脑鞘脂变化之间的关系，尤其是在APOE基因型背景下，仍不清楚。在这项研究中，我们分析了携带人类APOE3或APOE4变体、伴有或不伴有家族性AD突变（E3FAD和E4FAD）的转基因AD小鼠的血浆和大脑鞘脂谱。我们使用液相色谱 - 串联质谱法（LC - MS/MS），在2个月、4个月和6个月时检测血浆中以及在6个月时检测大脑皮质、海马体、纹状体和小脑中四大类（神经酰胺（Cers）、己糖神经酰胺（HexCers）、乳糖神经酰胺（LacCers）和鞘磷脂（SMs））共110种鞘脂。我们的研究结果表明，早期血浆鞘脂改变主要由APOE基因型驱动，而非AD病理。具体而言，与APOE3携带者相比，APOE4携带者的SM类物质显著增加，Cer类物质显著减少，且与年龄或AD基因型无关。经区域校正后，不同基因型的大脑脂质谱变化极小。然而，综合p值分析显示，主要是皮质鞘脂的组成存在APOE和EFAD依赖性差异。受试者工作特征曲线（ROC）分析表明，血浆鞘脂对APOE具有较高的鉴别能力，但对AD基因型则不然。这些发现表明，雌性5xFAD小鼠的早期血浆脂质谱受APOE基因型的影响比明显的AD病理更强，这可能反映了与APOE4相关AD风险相关的全身途径，而大脑中与早期疾病相关的变化似乎较为细微且具有区域特异性。这些结果强调了在早期AD脂质组学研究以及外周脂质生物标志物解读中考虑APOE基因型的重要性。

REF: van Kruining D, Losen M, Dehairs J, et al. Early plasma ceramide and sphingomyelin levels reflect APOE genotype but not familial Alzheimer's disease gene mutations in female 5xFAD mice, with brain-region specific sphingolipid alterations. Neurobiol Dis. 2025;210:106923. doi:10.1016/j.nbd.2025.106923 PMID: 40253012

Manifold functions of Mediator complex in neurodevelopmental disorders

中介体复合物在神经发育障碍中的多种功能

Neurodevelopmental disorders (NDDs) encompass a diverse range of impairments affecting brain development and functions, often presenting as deficits in motor skills, cognitive abilities, language development and neuropsychiatric health. The emergence of next-generation sequencing has unveiled numerous genetic variants linked to NDDs, implicating molecular pathways involved in essential neuronal processes such as synaptic plasticity, neuronal architecture and proteostasis. Central to these processes is the Mediator complex, a highly conserved multi-subunit assembly crucial for RNA polymerase II (Pol II)-dependent transcription. The Mediator functions as a key regulator of gene expression, playing a pivotal role in coordinating cellular processes essential for neuronal differentiation and developmental signaling cascades. Increasingly evidence has shown that its dysfunction is highly associated with the pathogenesis of NDDs. This review aims to comprehensively examine the structural and functional characteristics of individual mediator subunits. We will focus on clinical case reports and recent preclinical studies that highlight the connection between genetic abnormalities in the Mediator complex and specific neurodevelopmental phenotypes, ultimately guiding the development of enhanced diagnostic tools and therapeutic interventions. Furthermore, this review will advance our understanding of the general role transcriptional regulation plays in the etiology of NDDs.

神经发育障碍（NDDs）涵盖了一系列不同类型的损害，这些损害会影响大脑发育和功能，常表现为运动技能、认知能力、语言发育和神经精神健康方面的缺陷。下一代测序技术的出现揭示了众多与NDDs相关的基因变异，这些变异涉及突触可塑性、神经元结构和蛋白质稳态等重要神经元过程的分子通路。在这些过程中起核心作用的是中介体复合物，这是一种高度保守的多亚基组装体，对RNA聚合酶II（Pol II）依赖性转录至关重要。中介体作为基因表达的关键调节因子，在协调神经元分化和发育信号级联所必需的细胞过程中起着关键作用。越来越多的证据表明，其中介体功能障碍与NDDs的发病机制高度相关。本综述旨在全面研究各个中介体亚基的结构和功能特征。我们将重点关注临床病例报告和近期的临床前研究，这些研究凸显了中介体复合物的基因异常与特定神经发育表型之间的联系，最终为开发更有效的诊断工具和治疗干预措施提供指导。此外，本综述将增进我们对转录调控在NDDs病因中总体作用的理解。

REF: Li YW, Tu SX, Li ZX, Ding YQ, Hu L. Manifold functions of Mediator complex in neurodevelopmental disorders. Neurobiol Dis. 2025;210:106913. doi:10.1016/j.nbd.2025.106913 PMID: 40246246

Differences in transcriptome characteristics and drug repositioning of Alzheimer's disease according to sex

阿尔茨海默病转录组特征及药物重定位的性别差异

Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear. The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.

先前的研究表明，在阿尔茨海默病（AD）的流行病学、病理生理学、临床表现和治疗反应方面存在显著的性别差异。然而，AD中与性别相关的转录组差异仍不清楚。AD男性和女性患者外周血转录组以及前额叶皮质单细胞转录组的特征存在显著差异，这为未来AD的性别分层治疗提供了依据。

REF: Shi J, Zhang M, Hu Y, et al. Differences in transcriptome characteristics and drug repositioning of Alzheimer's disease according to sex. Neurobiol Dis. 2025;210:106909. doi:10.1016/j.nbd.2025.106909 PMID: 40220916

Cortical thickness and structural covariance network alterations in cerebral amyloid angiopathy: A graph theoretical analysis

脑淀粉样血管病中的皮质厚度和结构协方差网络改变：一项图论分析

This study investigates large-scale brain network alterations in cerebral amyloid angiopathy (CAA) using structural covariance network (SCN) analysis and graph theory based on 7 T MRI. SCN analysis combined with graph theory offers a valuable approach for understanding disease-related connectivity disruptions and may contribute to the development of network-based biomarkers for CAA.

本研究基于 7T 磁共振成像（MRI），采用结构协变网络（SCN）分析和图论方法，探究脑淀粉样血管病（CAA）患者的大规模脑网络改变。SCN 分析结合图论为理解与疾病相关的连接中断提供了一种有价值的方法，可能有助于开发基于网络的 CAA 生物标志物。

REF: Lin Y, Gao B, Du Y, Li M, Liu Y, Zhao X. Cortical thickness and structural covariance network alterations in cerebral amyloid angiopathy: A graph theoretical analysis. Neurobiol Dis. 2025;210:106911. doi:10.1016/j.nbd.2025.106911 PMID: 40239845

Exploring potential key genes and disease mechanisms in early-onset genetic epilepsy via integrated bioinformatics analysis

通过整合生物信息学分析探索早发性遗传性癫痫的潜在关键基因和疾病机制

Epilepsy is a severe common neurological disease affecting all ages. Epilepsy with onset before the age of 5 years, designated early-onset epilepsy (EOE), is of special importance. According to previous studies, genetic factors contribute significantly to the pathogenesis of EOE that remains unclear and must be explored. So, a list of 229 well-selected EOE-associated genes expressed in the brain was created for the investigation of genetic factors and molecular mechanisms involved in its pathogenesis. Enrichment analysis showed that among significant pathways were nicotine addiction, GABAergic synapse, synaptic vesicle cycle, regulation of membrane potential, cholinergic synapse, dopaminergic synapse, and morphine addiction. Performing an integrated analysis as well as protein-protein interaction network-based approaches with the use of GO, KEGG, ClueGO, cytoHubba and 3 network metrics, 12 hub genes were identified, seven of which, CDKL5, GABRA1, KCNQ2, KCNQ3, SCN1A, SCN8A and STXBP1, were identified as key genes (via Venn diagram analysis). These key genes are mostly enriched in SNARE interactions in vesicular transport, regulation of membrane potential and synaptic vesicle exocytosis. Clustering analysis of the PPI network via MCODE showed significant functional modules, indicating also other pathways such as N-Glycan biosynthesis and protein N-linked glycosylation, retrograde endocannabinoid signaling, mTOR signaling and aminoacyl-tRNA biosynthesis. Drug-gene interaction analysis identified a number of drugs as potential medications for EOE, among which the non-FDA approved drugs azetukalner (under clinical development), indiplon and ICA-105665 and the FDA approved drugs retigabine, ganaxolone and methohexital.

癫痫是一种严重的常见神经系统疾病，影响所有年龄段人群。5岁前发病的癫痫，即早发型癫痫（EOE），尤为重要。根据以往研究，遗传因素在EOE发病机制中起着重要作用，但其发病机制仍不清楚，有待进一步探索。因此，我们精心挑选了229个在大脑中表达的与EOE相关的基因，用于研究其发病机制中的遗传因素和分子机制。富集分析显示，显著的通路包括尼古丁成瘾、γ-氨基丁酸（GABA）能突触、突触囊泡循环、膜电位调节、胆碱能突触、多巴胺能突触和吗啡成瘾。通过使用基因本体论（GO）、京都基因与基因组百科全书（KEGG）、ClueGO、cytoHubba和3种网络指标进行综合分析以及基于蛋白质 - 蛋白质相互作用（PPI）网络的方法，确定了12个枢纽基因，其中7个基因，即CDKL5、GABRA1、KCNQ2、KCNQ3、SCN1A、SCN8A和STXBP1，被确定为关键基因（通过维恩图分析）。这些关键基因主要富集于囊泡运输中的可溶性N - 乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）相互作用、膜电位调节和突触囊泡胞吐作用。通过分子复合物检测（MCODE）对PPI网络进行聚类分析，显示出显著的功能模块，同时也表明存在其他通路，如N - 聚糖生物合成和蛋白质N - 糖基化、内源性大麻素逆行信号传导、哺乳动物雷帕霉素靶蛋白（mTOR）信号传导和氨酰 - tRNA生物合成。药物 - 基因相互作用分析确定了一些药物为EOE的潜在治疗药物，其中包括非美国食品药品监督管理局（FDA）批准的药物阿泽图卡尔纳（正在临床开发中）、英地普隆和ICA - 105665，以及FDA批准的药物瑞替加滨、甘氨雄酮和甲己炔巴比妥。

REF: Boulaki V, Efthimiopoulos S, Moschonas NK, Spyrou GΜ. Exploring potential key genes and disease mechanisms in early-onset genetic epilepsy via integrated bioinformatics analysis. Neurobiol Dis. 2025;210:106888. doi:10.1016/j.nbd.2025.106888 PMID: 40180227

Conservation of strain properties of bank vole-adapted chronic wasting disease in the absence of glycosylation and membrane anchoring

在无糖基化和膜锚定的情况下，适应于欧旅鼠的慢性消耗性疾病毒株特性的保留

Prion disease phenotypes (prion strains) are primarily determined by the specific misfolded conformation of the cellular prion protein (PrPC). However, post-translational modifications, including glycosyl phosphatidyl inositol (GPI) membrane anchoring and glycosylation, may influence strain characteristics. We investigated whether these modifications are essential for maintaining the unique properties of bank vole-adapted Chronic Wasting Disease (CWD-vole), the fastest known prion strain. Using a novel transgenic mouse model expressing I109 bank vole PrPC lacking the GPI anchor and largely devoid of glycans, we performed serial passages of CWD-vole prions. Despite elongated initial incubation periods, the strain maintained 100 % attack rate through three passages. Although the pathological phenotype showed characteristic GPI-less features, including abundant extracellular plaque formation, three subsequent serial passages in fully glycosylated and GPI-anchored bank vole I109 PrPC expressing transgenic mice TgVole (1×) demonstrated that the strain's distinctive rapid propagation properties were preserved. These findings suggest that neither GPI anchoring nor glycosylation are essential for maintaining CWD-vole strain properties, supporting the concept that strain characteristics are primarily encoded in the protein's misfolded structure.

朊病毒疾病表型（朊病毒毒株）主要由细胞型朊蛋白（PrPC）的特定错误折叠构象决定。然而，包括糖基磷脂酰肌醇（GPI）膜锚定和糖基化在内的翻译后修饰可能会影响毒株特征。我们研究了这些修饰对于维持已知传播速度最快的朊病毒毒株——适应于银行田鼠的慢性消耗性疾病毒株（CWD - 田鼠毒株）的独特特性是否必不可少。我们利用一种新型转基因小鼠模型，该模型表达缺乏GPI锚且基本无糖基化的109位为异亮氨酸（I109）的银行田鼠PrPC，对CWD - 田鼠朊病毒进行了连续传代。尽管初始潜伏期延长，但该毒株在三次传代中仍保持了100%的发病率。虽然病理表型呈现出特征性的无GPI特征，包括大量细胞外斑块形成，但随后在表达完全糖基化且有GPI锚定的银行田鼠I109 PrPC的转基因小鼠TgVole（1×）中进行的三次连续传代表明，该毒株独特的快速传播特性得以保留。这些发现表明，GPI锚定和糖基化对于维持CWD - 田鼠毒株特性并非必不可少，支持了毒株特征主要编码于蛋白质错误折叠结构中的观点。

REF: Vidal E, Eraña H, Charco JM, et al. Conservation of strain properties of bank vole-adapted chronic wasting disease in the absence of glycosylation and membrane anchoring. Neurobiol Dis. 2025;210:106894. doi:10.1016/j.nbd.2025.106894 PMID: 40220915

Contributions of major tau kinase activation and phospho-tau accumulation to cortical and hippocampal tangle formation and cognition in older adults

主要tau蛋白激酶激活和磷酸化tau蛋白积累对老年人皮质和海马神经原纤维缠结形成及认知功能的影响

Aberrant activation of tau kinases (tauK) has been proposed as a major step in tau hyperphosphorylation and misfolding, and subsequent formation of neurofibrillary tangles (NFT) in Alzheimer's disease (AD). However, evidence of tauK hyperactivation in actual AD brains is scarce and inconsistent, and their role in age-related cognitive decline remains undocumented. We evaluated activated/inhibited species of CDK5/p35/p25, GSK3α/β, and ERK1/2 as well as ten tau/phospho-tau (ptau) peptides (mapping Ser202, Thr217, Ser262, Ser305, and Ser404 phospho-residues) by Western blot or selected reaction monitoring proteomics, respectively, in postmortem dorsolateral prefrontal cortex (DLPFC) and hippocampal samples of 150 participants from the Rush Memory and Aging Project (MAP). Regression models and mediation analyses assessed the contributions of these variables to tau phosphorylation, NFT deposition and antemortem cognitive status of MAP participants. Surprisingly, greater p25 and p35 (indices for CDK5 activation) and lower pSer21/9-GSK3α/β (inhibited species) immunodensities were associated with lower ptau peptide amounts. Individuals with higher p25 cortical densities displayed better cognitive outcomes, particularly working memory. Statistical mediation analyses indicated that the beneficial effect of CDK5/p25 on cognition was mediated by lower densities of phospho-Thr217-tau and NFT deposition in DLPFC, and also identified Thr217 and Ser262 as the ptau sites with greatest influence in both NFT accumulation and cognitive impairment. The present data suggest that tau hyperphosphorylation, tangle deposition, and the subsequent cognitive impairment do not rely on aberrant activation of major tauKs. Additionally, novel evidence was provided for the beneficial contribution of cortical CDK5/p25 to the maintenance of working memory.

在阿尔茨海默病（AD）中，tau激酶（tauK）的异常激活被认为是tau蛋白过度磷酸化和错误折叠，以及随后神经原纤维缠结（NFT）形成的关键步骤。然而，在实际的AD大脑中，tauK过度激活的证据稀少且不一致，其在与年龄相关的认知衰退中的作用也尚无定论。我们分别通过蛋白质印迹法或选择性反应监测蛋白质组学技术，评估了150名来自拉什记忆与衰老项目（MAP）参与者的死后背外侧前额叶皮质（DLPFC）和海马样本中CDK5/p35/p25、GSK3α/β和ERK1/2的激活/抑制形式，以及十种tau/磷酸化tau（ptau）肽段（定位在Ser202、Thr217、Ser262、Ser305和Ser404磷酸化位点）。通过回归模型和中介分析评估了这些变量对MAP参与者的tau蛋白磷酸化、NFT沉积和生前认知状态的影响。令人惊讶的是，较高的p25和p35（CDK5激活指标）免疫密度以及较低的pSer21/9 - GSK3α/β（抑制形式）免疫密度与较低的ptau肽段含量相关。皮质p25密度较高的个体表现出更好的认知结果，尤其是工作记忆。统计中介分析表明，CDK5/p25对认知的有益作用是通过降低DLPFC中磷酸化Thr217 - tau的密度和NFT沉积来实现的，还确定了Thr217和Ser262是对NFT积累和认知障碍影响最大的ptau位点。目前的数据表明，tau蛋白过度磷酸化、缠结沉积以及随后的认知障碍并不依赖于主要tauK的异常激活。此外，还为皮质CDK5/p25对维持工作记忆的有益作用提供了新的证据。

REF: Hernández-Hernández E, Petyuk VA, Valor-Blanquer J, et al. Contributions of major tau kinase activation and phospho-tau accumulation to cortical and hippocampal tangle formation and cognition in older adults. Neurobiol Dis. 2025;210:106924. doi:10.1016/j.nbd.2025.106924 PMID: 40254098

Dynamic shift in localization of UBE3A across developmental stages in an Angelman syndrome mouse model

安吉尔曼综合征小鼠模型中UBE3A在不同发育阶段的定位动态变化

The ubiquitin-proteasome pathway (UPP) plays a crucial role in cellular homeostasis by regulating protein degradation. UBE3A, an E3 ubiquitin ligase encoded by the UBE3A gene, is maternally expressed in neurons and linked to neurodevelopmental disorders such as Angelman syndrome (AS) and 15q11-q13 duplication syndrome (Dup15q syndrome). While UBE3A is predominantly nuclear in mature neurons, its dynamic subcellular localization across development and potential mitochondrial role remain poorly understood. Here, we investigate the developmental distribution of UBE3A among nuclear, mitochondrial, and cytosolic compartments in wild-type (WT) and AS mouse brains at embryonic (E16.5), early postnatal (P2), and adult stages. In wild-type neurons, UBE3A is initially distributed evenly across the cytoplasm, mitochondria, and nucleus at E16.5, but later shifts predominantly to the nucleus in adulthood, with a concomitant decline in mitochondrial localization. In contrast, UBE3A in AS shows an aberrant distribution at early developmental stages, reduced nuclear localization and enhanced cytosolic accumulation, and an altered developmental trajectory, with a persistent redistribution toward the cytosol and reduced nuclear accumulation. Our findings provide new insights into the developmental dynamic shift of UBE3A's subcellular localization and suggest a link between UBE3A dysfunction, mitochondrial abnormalities, and AS pathophysiology. Furthermore, these results suggest that in normal conditions, UBE3A has a functional role in mitochondria during early neurodevelopment, which may be disrupted in AS.

泛素 - 蛋白酶体途径（UPP）通过调节蛋白质降解在细胞稳态中起着至关重要的作用。UBE3A是由UBE3A基因编码的一种E3泛素连接酶，在神经元中由母系表达，并且与诸如安吉尔曼综合征（AS）和15q11 - q13重复综合征（Dup15q综合征）等神经发育障碍相关。虽然在成熟神经元中UBE3A主要定位于细胞核，但它在整个发育过程中的动态亚细胞定位以及潜在的线粒体作用仍知之甚少。在这里，我们研究了野生型（WT）和AS小鼠大脑在胚胎期（E16.5）、出生早期（P2）和成年阶段，UBE3A在细胞核、线粒体和胞质区室中的发育分布情况。在野生型神经元中，在E16.5时，UBE3A最初均匀分布于细胞质、线粒体和细胞核，但在成年期主要转移至细胞核，同时线粒体定位相应减少。相比之下，AS中的UBE3A在发育早期表现出异常分布，核定位减少，胞质积累增加，并且发育轨迹发生改变，持续向胞质重新分布，核积累减少。我们的研究结果为UBE3A亚细胞定位的发育动态变化提供了新的见解，并提示UBE3A功能障碍、线粒体异常与AS病理生理学之间存在联系。此外，这些结果表明在正常情况下，UBE3A在神经发育早期的线粒体中具有功能作用，而在AS中这一作用可能会被破坏。

REF: Gupta PK, Feuermann Y, Kaphzan H. Dynamic shift in localization of UBE3A across developmental stages in an Angelman syndrome mouse model. Neurobiol Dis. 2025;210:106912. doi:10.1016/j.nbd.2025.106912 PMID: 40250721