Experimental Neurology最新文献_第2页

Integrated miRNA-proteomic profiling identifies chronic vesicle-trafficking and proteostasis disruptions after mild traumatic brain injury 综合mirna -蛋白质组学分析鉴定轻度创伤性脑损伤后的慢性囊泡运输和蛋白质平衡中断

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-26 DOI: 10.1016/j.expneurol.2026.115652

Hamad Yadikar , Mubeen A. Ansari

Background

Mild traumatic brain injury (mTBI) often produces persistent deficits, yet the molecular mechanisms driving chronic pathology remain undefined.

Objective

We aimed to identify mechanistic drivers of long-term dysfunction after mTBI by integrating proteomics, transcriptomics, and behavioral outcomes.

Methods

Adult rats were subjected to a modified Marmarou weight-drop mTBI model (diffuse closed-head injury) or a sham procedure. Cortical tissue was analyzed at 21 days post-injury (chronic phase) by quantitative proteomics and small RNA sequencing, while neurological and motor functions were tracked longitudinally (subacute to chronic phases). Key molecular changes were validated via Western blotting and RT-qPCR.

Results

mTBI induced widespread and persistent alterations in cortical protein expression, particularly affecting vesicle-trafficking and proteostasis-related pathways. Several proteins—including Rab11b, Dnm2, TIA1, Snx30, Sbf1, and Vma21—exhibited robust decreases across both proteomic and immunoblot analyses, indicating reproducible impairment of endosomal recycling and stress-response mechanisms. Cavin-2 and COMMD2 showed significant fold changes at the proteomic level but were not entirely validated and therefore remain preliminary observations. Differentially expressed miRNAs exhibited coordinated regulatory patterns, and integrated miRNA–protein signatures achieved high discriminatory performance (AUC > 0.95) in separating injured from control animals.

Conclusions

These findings demonstrate that even an mTBI causes enduring disruptions in protein homeostasis, vesicle trafficking, and post-transcriptional regulation, which correlate with chronic behavioral deficits. The injury-responsive networks identified provide a systems-level foundation for future mechanistic studies and highlight promising candidate biomarkers to improve mTBI diagnosis and monitoring.

背景：轻度创伤性脑损伤（mTBI）经常产生持续的缺陷，但驱动慢性病理的分子机制尚不清楚。目的：我们旨在通过整合蛋白质组学、转录组学和行为结果来确定mTBI后长期功能障碍的机制驱动因素。方法采用改良Marmarou减重mTBI模型（弥漫性闭合性头部损伤）或假手术治疗成年大鼠。通过定量蛋白质组学和小RNA测序分析损伤后21天（慢性期）的皮质组织，同时纵向追踪神经和运动功能（亚急性期至慢性期）。通过Western blotting和RT-qPCR验证关键分子变化。结果脑外伤引起皮质蛋白表达的广泛和持续改变，特别是影响囊泡运输和蛋白固定相关途径。包括Rab11b、Dnm2、TIA1、Snx30、Sbf1和vma21在内的几种蛋白质在蛋白质组学和免疫印迹分析中均表现出明显的减少，表明内体循环和应激反应机制的可重复性损伤。Cavin-2和COMMD2在蛋白质组学水平上显示出显著的折叠变化，但尚未完全验证，因此仍然是初步观察结果。差异表达的mirna表现出协调的调控模式，整合的mirna -蛋白特征在区分受伤动物和对照动物方面具有很高的歧视性（AUC > 0.95）。这些发现表明，即使是mTBI也会导致蛋白质稳态、囊泡运输和转录后调控的持续中断，这些都与慢性行为缺陷有关。确定的损伤反应网络为未来的机制研究提供了系统级基础，并突出了有希望的候选生物标志物，以改善mTBI的诊断和监测。

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引用次数: 0

A mouse model for cerebral/cortical visual impairment (CVI) impairs vision and disrupts the spatial frequency tuning of neurons in visual cortex 脑/皮质视觉障碍（CVI）小鼠模型损害视觉并破坏视觉皮层神经元的空间频率调谐。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-14 DOI: 10.1016/j.expneurol.2026.115648

Dana K. Oakes , Cecilia A. Attaway , Wenxin Zeng , Jun Cai , William Guido , Aaron W. McGee

Cerebral/cortical visual impairment (CVI) is a visual disorder often associated with perinatal hypoxic injury. The pathophysiology of CVI is poorly understood in part because of the lack of an animal model. Here we developed a murine model of CVI from existing rodent early postnatal hypoxia models for periventricular leukomalacia. Exposure to hypoxia during the equivalent to the human third trimester did not perturb gross motor function but caused severe impairments in binocular depth perception and visual acuity measured with behavioral assays. Impaired vision was associated with normal retinal function assessed with electroretinograms, but reduced size of the visual thalamus, and aberrant tuning for spatial frequency by populations of excitatory neurons in primary visual cortex calculated from in vivo calcium imaging experiments. This murine model of CVI provides a framework for triangulating circuit deficits with the severity of visual impairment and testing potential therapeutic interventions.

脑/皮质视觉障碍（CVI）是一种视觉障碍，通常与围产期缺氧损伤有关。由于缺乏动物模型，对CVI的病理生理学知之甚少。在这里，我们从现有的啮齿动物出生后早期心室周围白质软化缺氧模型中建立了小鼠CVI模型。在相当于人类妊娠晚期的缺氧环境中，大肌肉运动功能没有受到干扰，但双眼深度感知和视觉灵敏度受到严重损害。视力受损与视网膜电图评估的正常视网膜功能有关，但视丘脑尺寸减小，并且从体内钙成像实验中计算出初级视觉皮层兴奋性神经元群体对空间频率的异常调节。这种小鼠CVI模型为三角测量电路缺陷与视觉损伤的严重程度和测试潜在的治疗干预提供了一个框架。

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引用次数: 0

Molecular and biochemical insights into dysregulation of glycosphingolipid metabolism in a mouse model of lysosomal free sialic acid storage disorder 溶酶体游离唾液酸储存障碍小鼠模型中糖鞘脂代谢失调的分子和生化见解。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-22 DOI: 10.1016/j.expneurol.2026.115665

Marya S. Sabir , Mahin S. Hossain , Laura Pollard , Petcharat Leoyklang , Marjan Huizing , William A. Gahl , Frances M. Platt , May Christine V. Malicdan

Free sialic acid storage disorder (FSASD) is caused by pathogenic biallelic variants in SLC17A5, which encodes the lysosomal sialic acid exporter, sialin. FSASD is characterized by the accumulation of lysosomal free sialic acid, leading to either a severe, childhood-lethal form or a more slowly progressive neurodegenerative disorder associated with the p.Arg39Cys (p.R39C) variant, i.e., Salla disease. While dysregulated glycosphingolipid (GSL) metabolism has been observed in cellular models of FSASD, this study provides the first in vivo biochemical dissection of GSL metabolism in a knock-in mouse model harboring the Slc17a5 p.R39C variant. We employed an integrated multi-modal approach, including sialic acid quantification, exploratory untargeted lipidomics, HPLC-based GSL profiling, bulk transcriptomics, and 4-MU-based lysosomal enzyme activity assays in brain and peripheral tissues (liver and kidney). Exploratory untargeted lipidomic screening revealed region-dependent lipid alterations, with more pronounced changes in the cerebellum than in the forebrain. Pathway-level analyses indicated enrichment of lipid classes related to sphingolipid and GSL metabolism. Targeted biochemical analyses demonstrated that several GSL species accumulate predominantly in the brain, with minimal changes in peripheral tissues, whereas glucosylceramide levels were significantly reduced in all brain regions analyzed. Transcriptomic profiling identified dysregulation of several genes involved in GSL and sialic acid metabolism. Enzyme activity assays corroborated the transcriptomic findings, demonstrating increased activity of several lysosomal glycohydrolases, including neuraminidase 1/3/4 and β-hexosaminidase. Collectively, these findings highlight dysregulated GSL metabolism as a prominent biochemical consequence of sialin deficiency in vivo and highlight its putative role in FSASD neuropathology.

游离唾液酸储存障碍（fssd）是由SLC17A5的致病变异引起的，SLC17A5编码溶酶体唾液酸输出蛋白sialin。fssd的特点是溶酶体游离唾液酸的积累，导致严重的儿童致死形式或与p.a arg39cys （p.R39C）变异相关的进展较慢的神经退行性疾病，即Salla病。虽然在fssd的细胞模型中已经观察到糖鞘脂（GSL）代谢失调，但本研究首次在含有Slc17a5 p.R39C变体的敲入小鼠模型中对GSL代谢进行了体内生化解剖。我们采用了综合的多模式方法，包括唾液酸定量、探索性非靶向脂质组学、基于高效液相色谱的GSL分析、大量转录组学和基于4- mu的脑和外周组织（肝脏和肾脏）溶酶体酶活性测定。探索性非靶向脂质组学筛查显示区域依赖性脂质改变，小脑的变化比前脑的变化更明显。途径水平分析表明，与鞘脂和GSL代谢相关的脂类富集。有针对性的生化分析表明，几种GSL主要在大脑中积累，外周组织的变化很小，而葡萄糖神经酰胺水平在所有分析的大脑区域都显着降低。转录组学分析鉴定了参与GSL和唾液酸代谢的几个基因的失调。酶活性分析证实了转录组学的发现，表明几种溶酶体糖水解酶的活性增加，包括神经氨酸酶1/3/4和β-己糖氨酸酶。总的来说，这些发现强调了GSL代谢失调是体内唾液素缺乏的一个突出的生化后果，并强调了它在fssd神经病理学中的推测作用。

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引用次数: 0

Long-term continuous theta burst stimulation ameliorates L-DOPA-induced dyskinesia in Parkinsonian rats through modulation of the cerebello-thalamo-striatal circuit 长期连续θ波爆发刺激通过调节小脑-丘脑-纹状体回路改善左旋多巴诱导的帕金森大鼠运动障碍

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-29 DOI: 10.1016/j.expneurol.2026.115674

Ling Wang, Yixuan Wang, Shuo Yang, Yihua Bai, Xiang Wu, Qingfeng Sun, Yanping Hui, Libo Li, Hongfei Qiao, Qiaojun Zhang

Levodopa-induced dyskinesia (LID) is a debilitating complication of Parkinson's disease therapy. Emerging evidence suggests that the cerebellum is involved via cerebello -thalamo-striatal pathways.We first performed dual viral tracing to confirm cerebello-thalamo-striatal connectivity in a unilateral 6- hydroxydopamine rat model of LID. We then compared the efficacy of two cerebellar continuous theta burst stimulation (cTBS) protocols: a 2block protocol (14 days) and an intensified 3block protocol (10 days). Behavioral outcomes were assessed using the abnormal involuntary movement scale (AIMs). Local field potentials were recorded from the cerebellar dentate nucleus (DN) to characterize oscillatory variations. Striatal FosB expression was quantified as the molecular endpoint. Viral tracing confirmed the anatomical connectivity from the DN to the dorsolateral striatum via the parafascicular thalamus. Both the two protocols alleviated orolingual dyskinesia, with the 3block cTBS protocol demonstrated superior therapeutic efficacy (p < 0.001). Electrophysiological analysis revealed that LID was associated with reduced δ-band power and enhanced low-γ power in DN. Notably, cTBS normalized these aberrant oscillatory patterns by increasing δ power and decreasing pathological low-γ activity. The magnitude of δ power was negatively correlated with orolingual AIMs scores (r = −0.467, p = 0.021), whereas low-γ power was positively correlated with total dyskinesia severity (r = 0.551, p = 0.005) and orolingual AIMs scores (r = 0.581, p = 0.003). At the molecular level, cTBS normalized pathologically elevated striatal FosB expression in LID rats (p < 0.001). Collectively, these findings suggest that long-term cerebellar cTBS selectively ameliorates orolingual dyskinesia by modulating the cerebello-thalamo-striatal circuit.

左旋多巴诱导的运动障碍（LID）是帕金森病治疗的一种衰弱性并发症。新出现的证据表明小脑通过小脑-丘脑-纹状体通路参与。我们首先在单侧6-羟多巴胺大鼠LID模型中进行双病毒追踪以确认小脑-丘脑-纹状体的连通性。然后，我们比较了两种小脑连续θ波爆发刺激（cTBS）方案的疗效：2块方案（14天）和强化3块方案（10天）。使用异常不自主运动量表（AIMs）评估行为结果。从小脑齿状核（DN）记录局部场电位以表征振荡变化。以纹状体FosB表达为分子终点。病毒追踪证实了DN与背外侧纹状体通过束旁丘脑的解剖连接。两种方案均缓解了多语运动障碍，其中3block cTBS方案表现出更好的治疗效果（p < 0.001）。电生理分析显示，LID与DN的δ带功率降低和低γ功率增强有关。值得注意的是，cTBS通过增加δ功率和降低病理性低γ活性使这些异常振荡模式正常化。δ功率大小与运动障碍总分呈负相关（r = - 0.467, p = 0.021），低γ功率与运动障碍总分呈正相关（r = 0.551, p = 0.005），与运动障碍总分呈正相关（r = 0.581, p = 0.003）。在分子水平上，cTBS使LID大鼠病理性升高的纹状体FosB表达正常化（p < 0.001）。总的来说，这些发现表明，长期小脑cTBS通过调节小脑-丘脑-纹状体回路选择性地改善口语运动障碍。

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引用次数: 0

Activation of oligodendrocyte precursor cells triggers cognitive dysfunction and synaptic defects in SAE 少突胶质前体细胞的激活引发SAE的认知功能障碍和突触缺陷

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-27 DOI: 10.1016/j.expneurol.2026.115670

You Wu , Zhengdong Yang , Huiqing Liu , Jin Li , Renhuai Liu , Yi Li , Yu Chen , Binxiao Su

Sepsis-associated encephalopathy (SAE) is defined as a diffuse neurological dysfunction that occurs secondary to sepsis, in the absence of direct central nervous system infection, and is associated with high rates of incidence, mortality, and disability. Despite its clinical significance, the neuropathological mechanisms underlying SAE are not yet fully understood, making its pathogenesis a focal point of ongoing research. Oligodendrocyte precursor cells (OPCs), which are the most proliferative cell type within the central nervous system, primarily contribute to the generation of mature oligodendrocytes and are integral to myelination and the maintenance of myelin. Nevertheless, the role and pathological changes of OPCs during the acute phase of SAE remain inadequately characterized. This study illustrates that OPCs in the hippocampal CA1 region may undergo immune activation under SAE conditions, characterized by significantly elevated inflammatory transcription and phagocytic capacity. Additionally, activated OPCs in SAE mice may contribute to the synaptic pruning of neurons. By generating PDGFRa-Cre/ERT transgenic mice and conducting stereotactic injections of pAAV-EGFP-flex-DTA virus into the hippocampal CA1 region to selectively ablate OPCs, we observed a significant enhancement in cognitive function in SAE mice. This improvement is likely due to the alleviation of synaptic structural and functional impairments in neurons. Our findings indicate that OPCs play a critical role in the pathogenesis of SAE, highlighting their potential as a novel therapeutic target for this condition.

脓毒症相关脑病（SAE）被定义为继发于脓毒症的弥漫性神经功能障碍，在没有直接中枢神经系统感染的情况下，与高发病率、死亡率和致残率相关。尽管具有临床意义，但SAE的神经病理机制尚未完全了解，因此其发病机制是正在进行的研究的焦点。少突胶质前体细胞（OPCs）是中枢神经系统中最具增殖能力的细胞类型，主要有助于成熟少突胶质细胞的产生，是髓鞘形成和髓磷脂维持的组成部分。然而，OPCs在SAE急性期的作用和病理变化仍然没有充分的描述。本研究表明，SAE条件下海马CA1区的OPCs可能发生免疫激活，其特征是炎症转录和吞噬能力显著升高。此外，SAE小鼠中活化的OPCs可能有助于神经元的突触修剪。通过生成pdgfr - cre /ERT转基因小鼠，并将pAAV-EGFP-flex-DTA病毒立体定向注射到海马CA1区，选择性地消融OPCs，我们观察到SAE小鼠的认知功能显著增强。这种改善可能是由于神经元突触结构和功能损伤的减轻。我们的研究结果表明，OPCs在SAE的发病机制中起着关键作用，突出了它们作为这种疾病的新治疗靶点的潜力。

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引用次数: 0

Low-frequency TMS ameliorates neonatal hypoxia-ischemia injury by normalizing glutamatergic transmission in penumbra 低频经颅磁刺激通过调节半暗区谷氨酸能传递改善新生儿缺氧缺血损伤。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-25 DOI: 10.1016/j.expneurol.2026.115669

Ivan Goussakov, Sylvia Synowiec, Alexander Drobyshevsky

Perinatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in term neonates. The current standard of care, therapeutic hypothermia, provides only partial neuroprotection. This study investigates the potential of low-frequency transcranial magnetic stimulation (LF-TMS) as a novel non-pharmacological adjunct therapy by targeting a key pathological mechanism of HIE: a persistent, pathological increase in glutamatergic synaptic transmission, or hypoxic long-term potentiation.

Using a neonatal mouse model of hypoxia-ischemia, we administered a single session of LF-TMS 30 min after the hypoxic event. We then evaluated its effects on synaptic function via slice electrophysiology and on brain injury volume using serial MRI. Our results show that hypoxia-ischemia induced significant and lasting synaptic potentiation in the perilesional region of the somatosensory cortex. LF-TMS treatment successfully reduced this elevated glutamatergic response to control levels, suggesting a therapeutic mechanism similar to long-term depression and/or depotentiation by downregulating AMPA receptors.

LF-TMS provided significant neuroprotection, as demonstrated by reductions in volumes of the ischemic core and penumbra 48 h after the injury. LF-TMS did not alter excitability in sham-treated mice, confirming its safety as a targeted intervention for pathological conditions without affecting normal brain function. This study supports that LF-TMS is a promising neuroprotective strategy that mitigates brain injury in a neonatal hypoxia-ischemia model.

围产期缺氧缺血性脑病（HIE）是足月新生儿发病和死亡的主要原因。目前的护理标准，治疗性低温，只能提供部分神经保护。本研究探讨了低频经颅磁刺激（LF-TMS）作为一种新的非药物辅助治疗的潜力，通过针对HIE的一个关键病理机制：持续的、病理性的谷氨酸突触传递增加，或缺氧长期增强。使用新生小鼠缺氧缺血模型，我们在缺氧事件后30 min给予单次LF-TMS。然后，我们通过切片电生理评估其对突触功能的影响，并通过序列MRI评估其对脑损伤体积的影响。我们的研究结果表明，缺氧缺血在体感觉皮层的病灶周围区域诱导了显著和持久的突触增强。LF-TMS治疗成功地将这种升高的谷氨酸反应降低到控制水平，表明其治疗机制类似于通过下调AMPA受体的长期抑郁和/或去强化。LF-TMS提供了显著的神经保护作用，损伤后48 h缺血核心和半暗带的体积减少。LF-TMS没有改变假药治疗小鼠的兴奋性，证实了其作为病理条件的靶向干预的安全性，而不影响正常的脑功能。本研究支持LF-TMS是一种很有前途的神经保护策略，可以减轻新生儿缺氧缺血模型的脑损伤。

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引用次数: 0

Neuropathic pain after spinal cord injury: Mechanisms, animal models and pain assessments 脊髓损伤后神经性疼痛：机制、动物模型和疼痛评估。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-02-04 DOI: 10.1016/j.expneurol.2026.115678

Zean Tao , Xiaoling Zhou , Lixia Jin , Nixi Xu , Yuanwu Cao , Zhaoyi Wu , Chang Jiang , Zixian Chen

Neuropathic pain after spinal cord injury (SCI-NP) often has lifelong and significant negative effects. Therefore, understanding its underlying mechanisms is a current research priority.

SCI-NP involves central sensitization, neuroinflammation and functional remodeling in the brain, hyperexcitability of primary sensory neurons, and peripheral–central interactions. The mechanism of SCI-NP at the spinal cord level is an important one to study. Glial cell activation and proinflammatory pathways in the spinal cord are the key drivers that lead to central sensitization at the spinal cord level, and they constitute the main mechanisms of current research. However, the mechanism of SCI-NP remains unclear, mainly because of the lack of standardized and uniform animal models in preclinical studies.

Animal models provide a basis for the mechanistic study of SCI-NP, but the stability and repeatability of these models pose problems. Behavioral evaluation of animal models of SCI-NP has focused on mechanical and heat-induced pain thresholds, but this phenotype is different from the clinical diagnostic criteria of SCI-NP in patients, which includes at least four positive signs according to the DN4 scale. Electrophysiological recordings, especially from spinal dorsal horn neurons and dorsal root ganglia neurons, provide important support for SCI-NP research.

In summary, the development of SCI-NP involves a complex pathological process, and its mechanisms remain incompletely understood. Existing models and detection methods require refinement. This review focuses on the research progress in this field and looks forward to future research directions.

脊髓损伤后神经性疼痛（SCI-NP）通常具有终生和显著的负面影响。因此，了解其潜在机制是当前的研究重点。SCI-NP涉及中枢致敏、大脑的神经炎症和功能重塑、初级感觉神经元的高兴奋性以及外周-中枢相互作用。SCI-NP在脊髓水平的作用机制是一个重要的研究方向。脊髓中的神经胶质细胞活化和促炎通路是导致脊髓水平中枢致敏的关键驱动因素，也是当前研究的主要机制。然而，SCI-NP的机制尚不清楚，主要原因是临床前研究缺乏标准化和统一的动物模型。动物模型为SCI-NP的机制研究提供了基础，但这些模型的稳定性和可重复性存在问题。SCI-NP动物模型的行为评估主要集中在机械和热致疼痛阈值上，但这种表型与SCI-NP患者的临床诊断标准不同，临床诊断标准根据DN4量表至少包括4个阳性体征。脊髓背角神经元和背根神经节神经元的电生理记录为SCI-NP研究提供了重要支持。综上所述，SCI-NP的发展涉及一个复杂的病理过程，其机制尚不完全清楚。现有的模型和检测方法需要改进。本文综述了该领域的研究进展，并展望了未来的研究方向。

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引用次数: 0

Ectopically overexpressed glycine transporter 2 contributes to epileptogenesis in DEPDC5-related epilepsy 异位过表达的甘氨酸转运蛋白2参与depdc5相关癫痫的发生。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-24 DOI: 10.1016/j.expneurol.2026.115668

Tao Yang , Rajat Banerjee , Mirte Scheper , Mi Jiang , Steven Dai , Eleonora Aronica , Yu Wang

Loss-of-function mutations in DEPDC5 (DEP domain-containing protein 5), a critical negative regulator of mTORC1 (mechanistic Target of Rapamycin Complex 1), are often identified in patients with refractory epilepsy. To understand its underlying pathogenesis and develop novel therapeutics, we used a highly clinically relevant rat model of DEPDC5-related epilepsy and resected human patient tissues to profile the molecular architecture in the dysplastic cortex. We report here that Slc6a5 (solute carrier family 6 member 5 gene), a marker gene for glycinergic inhibitory neurons, is ectopically overexpressed in mutant excitatory neurons in both experimental animal and human tissues. Using CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) in utero electroporation (IUE) to simultaneously knock out Depdc5 and Slc6a5 in forebrain excitatory neurons reduces seizure frequency and duration. These data suggest that SLC6A5 plays an important role in the epileptogenesis of DEPDC5-related epilepsy, although the underlying mechanisms remain unclear.

DEPDC5 （DEP结构域蛋白5）是mTORC1（雷帕霉素复合体1的机制靶点）的关键负调节因子，其功能缺失突变常在难固性癫痫患者中发现。为了了解其潜在的发病机制并开发新的治疗方法，我们使用了一个具有高度临床相关性的大鼠depdc5相关癫痫模型，并切除了人类患者组织来分析发育不良皮层的分子结构。我们在这里报道Slc6a5（溶质载体家族6成员5基因）是甘氨酸能抑制性神经元的标记基因，在实验动物和人类组织中突变的兴奋性神经元中异位过表达。在子宫电穿孔（IUE）中使用CRISPR （Clustered Regularly Interspaced Short Palindromic Repeats）同时敲除前脑兴奋性神经元中的Depdc5和Slc6a5，可减少癫痫发作的频率和持续时间。这些数据表明，SLC6A5在depdc5相关癫痫的癫痫发生中起重要作用，尽管其潜在机制尚不清楚。

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引用次数: 0

β-1, 3-galactosyltransferase 2 promotes cerebral angiogenesis and neurological recovery during the ischemic repair phase through glycosylation modification of TGF-βR(II)/ALK1 β- 1,3 -半乳糖转移酶2通过TGF-βR(II)/ALK1的糖基化修饰促进缺血修复期脑血管生成和神经系统恢复

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-01-19 DOI: 10.1016/j.expneurol.2026.115651

Chang Liu , Yao Ma , Jiachen Li , Yunhao Xu , Meixuan Li , Hong Li , Zongze Li , Zhanyou Wang , Jia Liang , Peng Wang

β-1,3-galactosyltransferase 2 (B3galt2) has been increasingly recognized as an essential mediator in the pathogenesis of ischemic stroke (IS); nonetheless, its exact functional role has not been fully elucidated. This research aimed to clarify the regulatory mechanisms by which B3galt2 influences cerebral angiogenesis during the repair phase following ischemic injury. A mouse model of cerebral ischemia/reperfusion (I/R) injury was generated by subjecting animals to 1-h middle cerebral artery occlusion (MCAO), succeeded by reperfusion for varying time intervals. Recombinant human B3galt2 (rh-B3galt2) was administered intranasally beginning on day one post-injury and continued until tissue collection. Experimental outcomes revealed that rh-B3galt2 substantially diminished brain atrophy and enhanced neurological recovery during the repair phase of ischemia. Furthermore, rh-B3galt2 facilitated angiogenesis through increased expression of vascular endothelial growth factor A (VEGFA) and the tight junction proteins, occludin and claudin 5. Moreover, rh-B3galt2 activated the TGF-βR(II)/ALK1/Smad1/5 pathway. The galactosylation levels of TGF-βR(II) and ALK1 were increased after rh-B3galt2 treatment, suggesting that B3galt2 may regulate TGF-βR(II) and ALK1 through glycosylation modification. Moreover, the advantageous impacts of rh-B3galt2 on reducing brain atrophy and alleviating neurological deficits were reversed upon treatment with the ALK1 inhibitor, ML347. ML347 also counteracted the angiogenic promotion induced by rh-B3galt2, demonstrating that inhibition of ALK1 abolishes the protective benefits mediated by rh-B3galt2. Collectively, the results indicated that rh-B3galt2 significantly promotes angiogenesis and neurological function recovery during the cerebral ischemic repair stage, likely by regulating TGF-βR(II)/ALK1/Smad1/5 signaling pathway through glycosylation modification.

β-1,3-半乳糖转移酶2 （B3galt2）越来越被认为是缺血性卒中（IS）发病机制的重要介质；然而，其确切的功能作用尚未完全阐明。本研究旨在阐明B3galt2在缺血性损伤修复阶段影响脑血管新生的调控机制。采用大脑中动脉阻断（MCAO） 1h，再灌注不同时间间隔的方法，建立脑缺血再灌注（I/R）损伤小鼠模型。重组人B3galt2 （rh-B3galt2）从损伤后第一天开始经鼻给药，一直持续到组织收集。实验结果显示，在缺血修复阶段，rh-B3galt2显著减少脑萎缩，促进神经恢复。此外，rh-B3galt2通过增加血管内皮生长因子A （VEGFA）和紧密连接蛋白occludin和claudin 5的表达促进血管生成。此外，rh-B3galt2激活了TGF-βR(II)/ALK1/Smad1/5通路。rh-B3galt2处理后TGF-βR（II）和ALK1半乳糖基化水平升高，提示B3galt2可能通过糖基化修饰调节TGF-βR（II）和ALK1。此外，rh-B3galt2在减少脑萎缩和减轻神经功能缺陷方面的有利作用在使用ALK1抑制剂ML347治疗后被逆转。ML347还抵消了rh-B3galt2诱导的血管生成促进作用，表明对ALK1的抑制消除了rh-B3galt2介导的保护作用。综上所述，rh-B3galt2可能通过糖基化修饰调控TGF-βR(II)/ALK1/Smad1/5信号通路，显著促进脑缺血修复阶段血管生成和神经功能恢复。

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引用次数: 0

DLK inhibition has sex-specific effects on neuroprotection and locomotor recovery after spinal cord injury DLK抑制对脊髓损伤后的神经保护和运动恢复具有性别特异性作用。

IF 4.2 2区医学 Q1 NEUROSCIENCES

Experimental Neurology

Pub Date : 2026-05-01 Epub Date: 2026-02-08 DOI: 10.1016/j.expneurol.2026.115681

John C. Aldrich , Samantha M. Alman , Sydney E. Lee , Ashley R. Scheinfeld , Chelsea C. Zhang , Averi L. Pike , Fiona C. Bremner , Olivia Calderon , Sunil Goodwani , William J. Ray , Andrew D. Gaudet

Spinal cord injury (SCI) causes devastating functional deficits, in part due to neuroinflammation, oxidative stress, and excitotoxicity that drive death of lesion-adjacent viable neurons. Dual leucine zipper kinase (DLK) is a neuron-enriched kinase that responds to cellular stress by activating the c-Jun N-terminal kinase (JNK) pathway, driving both stress-responsive gene expression and neuronal apoptosis. We hypothesized that SCI would robustly activate DLK signaling and that acute pharmacological inhibition of DLK would suppress JNK pathway activation, thereby enhancing neuroprotection and locomotor recovery in our mouse model of moderate contusion SCI. Using western blotting, we observed that SCI induced strong and sustained activation of the JNK pathway in the injured spinal cord starting at 4 h post-injury through 7 days. Complementary analysis of single-nucleus RNA-seq revealed that DLK expression is highly enriched in neurons across all injury phases. Following SCI, neurons exhibited robust, time-dependent upregulation of multiple DLK-responsive transcripts, consistent with sustained pathway activation during the acute and subacute periods. Systemic treatment with the selective DLK inhibitor IACS-52825 effectively suppressed intraspinal JUN activation in a dose-dependent manner. However, unexpectedly, treatment delayed functional recovery and expanded lesion volume by 71% in male mice with no significant effect in females. These findings highlight the complex roles of DLK signaling after SCI, revealing a need to understand the sex-specific molecular mechanisms that modulate injury outcomes. Future studies should further optimize timing, location, and cellular targeting of DLK therapeutic strategies to improve neuroprotection and neurologic recovery after SCI.

脊髓损伤（SCI）导致毁灭性的功能缺陷，部分原因是神经炎症、氧化应激和兴奋性毒性导致病变附近活神经元死亡。双亮氨酸拉链激酶（Dual leucine zipper kinase， DLK）是一种神经元富集激酶，通过激活c-Jun n-末端激酶（JNK）通路来响应细胞应激，驱动应激反应基因表达和神经元凋亡。我们假设脊髓损伤会强烈激活DLK信号，而DLK的急性药物抑制会抑制JNK通路的激活，从而增强中度挫伤脊髓小鼠模型的神经保护和运动恢复。通过western blotting，我们观察到脊髓损伤诱导损伤脊髓JNK通路的强烈和持续激活，从损伤后4 h开始持续7 天。单核RNA-seq的补充分析显示，DLK表达在所有损伤期的神经元中都高度富集。脊髓损伤后，神经元表现出多种dlk应答转录物的稳健、时间依赖性上调，这与急性和亚急性期持续的通路激活一致。选择性DLK抑制剂IACS-52825的全身治疗以剂量依赖的方式有效抑制了椎管内JUN的激活。然而，出乎意料的是，治疗延迟了雄性小鼠的功能恢复，并使病变体积扩大了71%，而对雌性小鼠没有显著影响。这些发现强调了脊髓损伤后DLK信号的复杂作用，揭示了了解调节损伤结果的性别特异性分子机制的必要性。未来的研究应进一步优化DLK治疗策略的时机、位置和细胞靶向性，以改善脊髓损伤后的神经保护和神经功能恢复。

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引用次数: 0