Molecular and Cellular Neuroscience最新文献_第3页

Neuroprotective effect of the peroxisome proliferator-activated receptor γ agonist lobeglitazone following intracerebral hemorrhage in rats. 过氧化物酶体增殖物激活受体γ激动剂洛贝列酮对脑出血大鼠的神经保护作用。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-09-01 Epub Date: 2025-07-10 DOI: 10.1016/j.mcn.2025.104030

Tae Jung Kim, Young-Ju Kim, Soo-Hyun Park, Youngjoon Kim, Sang-Bae Ko

Lobeglitazone, an oral antidiabetic medication, acts as a peroxisome proliferator-activated receptor γ (PPARγ) agonist and demonstrates neuroprotective effects. This study investigated beneficial effects and mechanisms of lobeglitazone treatment in an experimental intracerebral hemorrhage (ICH) rat model. ICH was induced in the left striatum of Sprague-Dawley rats by administration of 0.6 units of collagenase type IV. Rats with ICH were assigned randomly to three treatment groups: (1) control group, (2) lobeglitazone 2 mg/kg, and (3) lobeglitazone 4 mg/kg (N = 6, in each group). Medications were administered orally for 3 days following ICH. Outcomes were measured based on brain edema on the third day after ICH. Behavioral outcomes were evaluated on days 1, 3, 6, and 13 following ICH utilizing the modified neurological severity score (mNSS). On the third day after ICH, inflammatory cytokines were evaluated using western blotting, and inflammatory cells were examined through immunohistochemistry. Administration of lobeglitazone at a dosage of 4 mg/kg reduced brain edema significantly (15 %) in comparison to the control and 2 mg/kg (7 %) groups. Moreover, lobeglitazone administration at a dosage of 4 mg/kg suppressed infiltration of macrophages and neutrophils in perihematomal areas. Expression of several inflammatory cytokines, including interleukin-1 beta (IL-1b), extracellular signal-regulated kinase (ERK), and cyclooxygenase-2 (COX2) were also reduced. Regarding functional outcomes, a high dose of lobeglitazone (4 mg/kg) improved the mNSS significantly on days 3 and 13 after ICH. The results suggest that lobeglitazone, a PPARγ agonist, has potential neuroprotective effects on ICH by modulating brain edema and brain inflammation via IL-1β-ERK-COX-2 pathway inhibition.

洛贝格列酮是一种口服降糖药物，作为过氧化物酶体增殖物激活受体γ (PPARγ)激动剂，具有神经保护作用。本研究探讨了洛贝列酮对实验性脑出血（ICH）大鼠模型的有益作用及其机制。采用0.6 单位IV型胶原酶诱导sd - dawley大鼠左纹状体脑出血，将脑出血大鼠随机分为3组：(1)对照组，(2)洛贝列酮2 mg/kg，(3)洛贝列酮4 mg/kg （N = 6，每组）。脑出血后口服药物3 天。根据脑出血后第3天的脑水肿来衡量结果。使用改良神经严重程度评分（mNSS）评估ICH后第1、3、6和13天的行为结果。脑出血后第3天，采用免疫印迹法检测炎症因子，免疫组化法检测炎症细胞。与对照组和2 mg/kg组相比，给药剂量为4 mg/kg的洛贝列酮显著减少脑水肿（15 %）。此外，4 mg/kg剂量的洛贝列酮可抑制巨噬细胞和中性粒细胞在血肿周围的浸润。多种炎性细胞因子的表达，包括白细胞介素-1 β (IL-1b)、细胞外信号调节激酶（ERK）和环氧化酶-2 （COX2）也降低。在功能结果方面，高剂量洛贝列酮（4 mg/kg）在脑出血后第3天和第13天显著改善了mNSS。结果提示，PPARγ激动剂洛贝列酮通过抑制IL-1β-ERK-COX-2通路调节脑水肿和脑炎症，对脑出血具有潜在的神经保护作用。

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引用次数: 0

Eprosartan alleviates the traumatic brain injury-induced multi-organ dysfunction syndrome in mice via AT1R/SNS/HMGB1 blockade and PDL-1 modulation 依普沙坦通过阻断AT1R/SNS/HMGB1和调节PDL-1减轻小鼠外伤性脑损伤多器官功能障碍综合征。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-08-29 DOI: 10.1016/j.mcn.2025.104035

Manisha Thakur , Sunil Sharma , Neeru Vasudeva , Paras Saini , Deepika Lather , Deepak Deepak

Traumatic brain injury is not constrained only to the brain but delayed secondary events disturb the end organ functioning via intense response of three homeostatic mechanisms such as sympathetic activity, inflammation, and immunosuppression. Current study involved weight drop model to induce TBI in Swiss albino mice. Eprosartan was administered orally after 30–45 min post injury to mice in 0.35 mg/kg and 0.7 mg/kg doses. Mice were tested for neurobehavioral alterations and multiple organs, including brain, heart, lungs, liver, and kidney were excised for further edema, biochemical, inflammatory, catecholamine, gene expression and histopathological estimations at both acute and chronic phases of injury. Results highlighted that Epro improved neurobehavioral performance, maintained the BBB and lung integrity. It also ameliorated the oxidative stress as well as docking studies exhibited strong binding affinity of Epro for HMGB1 and PDL-1, that further supported by low tissue HMGB1 and serum IL-6 and TNF-α cytokines levels which halted the systemic hyperinflammation. Moreover, Epro treatment successfully restored the cardiac, hepatic and kidney function through stabilized serum biomarkers with declined plasma noradrenaline levels that subsides the sympathetic storm. Considerably, a bizarre cellular morphology was displayed by the organs in acute phase of injury whereas Epro reversed the morphological changes at chronic stage. Also, epro encouraged the PD-1/PDL-1 and IL-10 gene expression in the tissues that regulates immune response. Thus, it is concluded that Epro exerts its organ protective effect against MODS via AT₁/SNS pathway inhibition.

外伤性脑损伤不仅局限于大脑，延迟的继发性事件通过交感神经活动、炎症和免疫抑制等三种体内平衡机制的强烈反应扰乱终末器官的功能。目前研究采用减重模型诱导瑞士白化小鼠TBI。在小鼠损伤后30-45 min口服依泊沙坦，剂量分别为0.35 mg/kg和0.7 mg/kg。对小鼠进行神经行为改变测试，并在损伤的急性和慢性阶段切除多个器官，包括脑、心、肺、肝和肾，以进行进一步的水肿、生化、炎症、儿茶酚胺、基因表达和组织病理学评估。结果显示，Epro改善了神经行为表现，维持了血脑屏障和肺完整性。对接研究显示Epro对HMGB1和PDL-1具有较强的结合亲和力，这进一步得到了低组织HMGB1和血清IL-6和TNF-α细胞因子水平的支持，从而阻止了全身性高炎症。此外，Epro治疗通过稳定血清生物标志物，降低血浆去甲肾上腺素水平，使交感神经风暴消退，成功恢复了心脏、肝脏和肾脏功能。急性期各脏器细胞形态异常，而Epro可逆转慢性期脏器细胞形态的变化。此外，epro还促进了调节免疫反应的组织中PD-1/PDL-1和IL-10基因的表达。由此可见，Epro对MODS的器官保护作用是通过抑制AT1/SNS通路发挥的。

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引用次数: 0

Knockout of indoleamine 2,3-dioxygenase 1 gene expression improves depressive and anxiety-like phenotypes in a murine model of mild traumatic brain injury 敲除吲哚胺2,3-双加氧酶1基因表达可改善轻度创伤性脑损伤小鼠模型的抑郁和焦虑样表型。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-08-05 DOI: 10.1016/j.mcn.2025.104033

João Luís Vieira Monteiro de Barros , Caroline Amaral Machado , Ricardo Tadeu de Carvalho , Bruna da Silva Oliveira , Ingrid dos Santos Freitas , Lorena Taveira Nogueira , Giovana Cougo Ferreira , Heliana de Barros Fernandes , Brener Cunha Carvalho , Vivian Vasconcelos Costa , Antônio Lúcio Teixeira , Aline Silva de Miranda

Background

Indoleamine 2,3-dioxygenase (IDO) modulates the kynurenine pathway and may influence post-mild traumatic brain injury (mTBI) outcomes. This study tested whether IDO knockout (IDO-KO) mice exhibit distinct behavioral profiles and neurotrophic factor levels after a mTBI.

Methods

Male C57BL/6 WT and IDO-KO mice (10–12 weeks) underwent weight-drop-induced mTBI or sham procedures. Anxiety- and depression-like behaviors were assessed 72 h later via elevated plus maze and forced swim tests, respectively. Neurotrophic factors BDNF, NGF, NT3 and GDNF levels were measured by ELISA in the ipsilateral and contralateral prefrontal cortex and hippocampus.

Results

WT mice exhibited increased anxiety- and depressive-like behaviors post-mTBI, whereas IDO-KO mice did not show these behaviors. In parallel, mTBI increased BDNF levels in the ipsilateral hippocampus that were more pronounced in IDO-KO compared to WT. IDO-KO mice also exhibited a different pattern of NGF and GDNF compared to WT after mTBI.

Conclusion

IDO deficiency prevented mTBI-induced anxiety- and depressive-like behaviors and altered neurotrophic factor levels regionally. These findings implicate IDO in post-mTBI behavioral and neurotrophic responses, warranting further study of kynurenine pathway metabolites and downstream signaling to clarify the mechanism underlying the role of IDO in mTBI outcomes.

背景：吲哚胺2,3-双加氧酶（IDO）调节犬尿氨酸途径并可能影响轻度创伤性脑损伤（mTBI）后的预后。这项研究测试了IDO敲除（IDO- ko）小鼠在mTBI后是否表现出不同的行为特征和神经营养因子水平。方法：雄性C57BL/6 WT和IDO-KO小鼠（10-12 周）接受体重下降诱导的mTBI或假手术。焦虑和抑郁样行为在72 h后分别通过升高+迷宫和强迫游泳测试进行评估。ELISA法测定大鼠同侧、对侧前额叶皮层和海马中神经营养因子BDNF、NGF、NT3和GDNF水平。结果：WT小鼠在mtbi后表现出增加的焦虑和抑郁样行为，而IDO-KO小鼠没有表现出这些行为。同时，与WT相比，mTBI增加了IDO-KO同侧海马中的BDNF水平。与WT相比，mTBI后IDO-KO小鼠也表现出不同的NGF和GDNF模式。结论：IDO缺乏可预防mtbi诱导的焦虑和抑郁样行为，并局部改变神经营养因子水平。这些发现暗示IDO参与mTBI后的行为和神经营养反应，需要进一步研究犬尿氨酸途径代谢物和下游信号，以阐明IDO在mTBI结果中的作用机制。

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引用次数: 0

The glymphatic and meningeal lymphatic systems may converge, connecting traumatic brain injury progression with chronic traumatic encephalopathy onset 淋巴系统和脑膜淋巴系统可能会聚，将创伤性脑损伤的进展与慢性创伤性脑病的发病联系起来

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-07-23 DOI: 10.1016/j.mcn.2025.104031

Randy Bent Barker , Eda Karakaya , Didem Baran , Adviye Ergul , Kaan Yagmurlu , Mehmet Albayram , Onder Albayram

Chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease marked by perivascular deposition of hyperphosphorylated tau (P-tau), is strongly linked to repetitive concussive traumatic brain injuries (TBIs). Emerging evidence implicates disruptions in the clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) from the brain—specifically within the glymphatic and meningeal lymphatic systems—as a pivotal driver of disease onset and progression. TBI disrupts glymphatic ISF–CSF exchange, compromising the clearance of pathogenic proteins—including P-tau, TDP-43, and inflammatory mediators—while promoting perivascular accumulation and neuroinflammation. Simultaneously, meningeal lymphatic dysfunction impedes CSF drainage and sustains neuroimmune activation, further amplifying glymphatic failure. Developmental trajectories of these systems suggest age-dependent susceptibilities to injury, potentially shaping both acute outcomes and long-term neurodegenerative risk. Species-specific differences between rodents and humans in brain fluid clearance pathways add translational complexity, emphasizing the need for refined models. This review reconceptualizes CTE as a disorder driven by disrupted brain fluid clearance, highlighting the convergent roles of glymphatic and meningeal lymphatic dysfunction in linking TBI to chronic neurodegeneration and identifying therapeutic targets to restore clearance and resilience.

慢性创伤性脑病（CTE）是一种进行性神经退行性疾病，其特征是血管周围过度磷酸化的tau蛋白（P-tau）沉积，与重复性震荡创伤性脑损伤（tbi）密切相关。新出现的证据表明，脑内间质液（ISF）和脑脊液（CSF）的清除中断，特别是在淋巴和脑膜淋巴系统内，是疾病发生和进展的关键驱动因素。TBI破坏淋巴ISF-CSF交换，损害致病性蛋白（包括P-tau、TDP-43和炎症介质）的清除，同时促进血管周围积聚和神经炎症。同时，脑膜淋巴功能障碍阻碍脑脊液引流并维持神经免疫激活，进一步放大淋巴功能衰竭。这些系统的发育轨迹表明对损伤的年龄依赖性易感性，可能影响急性结果和长期神经退行性风险。啮齿类动物和人类在脑液清除途径上的物种特异性差异增加了翻译的复杂性，强调了改进模型的必要性。这篇综述将CTE重新定义为一种由脑液清除中断驱动的疾病，强调了淋巴和脑膜淋巴功能障碍在将TBI与慢性神经退行性变联系起来方面的共同作用，并确定了恢复清除和恢复能力的治疗靶点。

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引用次数: 0

Ubiquitous calpastatin overexpression in brain-injured mice attenuates motor and cognitive behavioral deficits without overt neuroprotection 脑损伤小鼠中普遍存在的钙pastatin过表达可减轻运动和认知行为缺陷，但没有明显的神经保护作用。

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-07-22 DOI: 10.1016/j.mcn.2025.104032

Kathleen M. Schoch , Dominic N. Nthenge-Ngumbau , Jennifer M. Brelsfoard , Gregory S. Hawk , Kathryn E. Saatman

Calpains are a family of calcium-dependent cysteine proteases that are activated within the brain minutes after a traumatic brain injury (TBI). Sustained calpain activation contributes to the secondary injury cascade of TBI and has been linked to neuronal and axonal degeneration and impairment of neurological function. Calpastatin is an endogenous protein encoded by the CAST gene which serves as a potent and highly selective inhibitor of calpains. This study investigates the potential of overexpressing human calpastatin (hCAST) via the ubiquitous prion protein promoter in a mouse model to alleviate TBI-induced brain damage and neurobehavioral dysfunction. Transgenic mice overexpressing hCAST and wildtype controls received a controlled cortical impact to induce contusive TBI or a sham injury. Overexpression of calpastatin significantly attenuated motor deficits over the first week in brain-injured mice. Visuospatial learning ability assessed in a Morris water maze on days 6 through 9 and novel object recognition on day 10 were impaired following TBI in wildtype mice. Both learning and memory function were improved in brain-injured hCAST overexpressing mice compared to wildtype mice. At 10 days post-injury brains were evaluated for cortical tissue damage and hippocampal neuron death. Analysis of Nissl-stained brain sections revealed no significant difference in the size of the cortical contusion between hCAST and wildtype animals. Similarly, hippocampal neurodegeneration associated with TBI was not modulated by hCAST overexpression. These findings demonstrate that inhibition of calpains aids in restoration of neurobehavioral function following TBI without protecting against cortical or hippocampal neuron death.

钙蛋白酶是一种钙依赖的半胱氨酸蛋白酶家族，在创伤性脑损伤（TBI）后的几分钟内被激活。持续的钙蛋白酶激活有助于TBI的继发性损伤级联，并与神经元和轴突变性和神经功能损害有关。钙pastatin是一种由CAST基因编码的内源性蛋白，是一种有效的高选择性钙蛋白酶抑制剂。本研究探讨了在小鼠模型中通过普遍存在的朊蛋白启动子过表达人钙pastatin （hCAST）以减轻tbi诱导的脑损伤和神经行为功能障碍的潜力。过表达hCAST的转基因小鼠和野生型对照小鼠接受有控制的皮质冲击，以诱导挫伤性脑损伤或假损伤。过表达calpastatin可显著减轻脑损伤小鼠第一周的运动缺陷。在Morris水迷宫中评估的视觉空间学习能力和在第10天评估的新物体识别能力在野生型小鼠TBI后受损。与野生型小鼠相比，hCAST过表达脑损伤小鼠的学习和记忆功能均得到改善。在损伤后10 天评估大脑皮质组织损伤和海马神经元死亡。nissl染色脑切片分析显示，hCAST与野生型动物皮质挫伤的大小无显著差异。同样，与TBI相关的海马神经退行性变不受hCAST过表达的调节。这些发现表明，抑制钙蛋白酶有助于脑外伤后神经行为功能的恢复，但不保护皮层或海马神经元的死亡。

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引用次数: 0

DAPK1 induces motor neuron apoptosis in hSOD1G93A-linked amyotrophic lateral sclerosis via regulating the Xiap/JNK pathway DAPK1通过调节Xiap/JNK通路诱导hsod1g93a相关肌萎缩性侧索硬化运动神经元凋亡

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-07-14 DOI: 10.1016/j.mcn.2025.104029

Xiaoli Su , Xingli Tan , Ying Wang , Weiwei Liang , Di Wang , Di Huo , Hongyong Wang , Yan Qi , Wenmo Zhang , Ling Han , Dongmei Zhang , Ming Wang , Jing Xu , Honglin Feng

Death-associated protein kinase 1 (DAPK1) is critically involved in regulating cell death in various neurodegenerative disorders. However, the role of DAPK1 in the pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. Here, we found that the expression of DAPK1 significantly increased in ALS, showing a negative correlation with miR-501-3p. Upregulating DAPK1 led to an increase in motor neuron apoptosis by inhibiting Xiap. Conversely, silencing of DAPK1 protected motor neurons against hSOD1^G93A-induced apoptosis by activating Xiap. Furthermore, we demonstrate that the neuroprotective impact of DAPK1-knockdown was inhibited by Embelin, an inhibitor of Xiap. These results suggest that modulating the DAPK1/Xiap signaling cascade protects motor neurons from apoptosis, indicating its potential as a therapeutic target in ALS. Significantly, these findings offer new directions for treatment options for ALS patients.

死亡相关蛋白激酶1 （DAPK1）在调节各种神经退行性疾病的细胞死亡中起关键作用。然而，DAPK1在肌萎缩性侧索硬化症（ALS）发病机制中的作用尚不清楚。这里，我们发现DAPK1在ALS中的表达显著升高，与miR-501-3p呈负相关。上调DAPK1通过抑制Xiap导致运动神经元凋亡增加。相反，DAPK1沉默通过激活Xiap保护运动神经元免受hsod1g93a诱导的凋亡。此外，我们证明了dapk1敲低的神经保护作用被Embelin（一种Xiap抑制剂）所抑制。这些结果表明，调节DAPK1/Xiap信号级联可以保护运动神经元免于凋亡，这表明它可能是ALS的治疗靶点。值得注意的是，这些发现为ALS患者的治疗选择提供了新的方向。

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引用次数: 0

Sex-specific neuroprotection: Does BDNF shield girls from autism? 性别特异性神经保护：BDNF能保护女孩远离自闭症吗？

IF 2.4 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-07-08 DOI: 10.1016/j.mcn.2025.104028

Takshashila Wankhade , Nayan Thakre , Manasi Tadas , Raj Katariya , Milind Umekar , Nandkishor Kotagale , Brijesh Taksande

Autism Spectrum Disorder (ASD) exhibits a clear male bias, with males being approximately four times more likely to be affected than females. This difference has sparked curiosity about possible neurological elements that provide protection to females. One such neurological element that has shown promise is brain-derived neurotrophic factor (BDNF), essential for neuronal development, synaptic plasticity, and neuroprotection. ASD may be less common in females due to increased BDNF levels, which may be influenced by sex-specific epigenetic control and estrogen hormone. Research studies indicate that increased baseline BDNF in females promotes neurodevelopmental resilience and mitigates the environmental and genetic risk factors linked to ASD. Also, this protective impact may be enhanced by the regulatory function of estrogen in BDNF expression and the interaction of BDNF with X-linked genes. The processes by which BDNF contributes to sex differences are still not well understood despite strong evidence. Interpreting results is made more difficult by the variability of ASD symptoms and variations in study methodologies. In addition to that, it is yet unknown whether increased BDNF levels represent compensatory processes or actually provide protection. Longitudinal studies that monitor BDNF expression across developmental stages and look at sex-specific treatment approaches that target BDNF pathways should be the main focus of future research. Thus, a thorough understanding of how BDNF prevents sex differences in ASD may pave the way for innovative strategies destined to diminish the risk of ASD. In this milieu, this review explores the current research, highlighting the complex relationship between sex differences, BDNF, and the incidence of ASD.

自闭症谱系障碍（ASD）表现出明显的男性偏见，男性受影响的可能性大约是女性的四倍。这一差异引发了人们对可能的神经学因素的好奇，这些因素为女性提供了保护。脑源性神经营养因子（brain-derived neurotrophic factor， BDNF）是其中一种显示出前景的神经学元素，它对神经元发育、突触可塑性和神经保护至关重要。由于BDNF水平升高，ASD在女性中可能不太常见，这可能受到性别特异性表观遗传控制和雌激素激素的影响。研究表明，女性基线BDNF增加可促进神经发育恢复力，并减轻与ASD相关的环境和遗传风险因素。此外，雌激素对BDNF表达的调节功能以及BDNF与x连锁基因的相互作用可能会增强这种保护作用。尽管有强有力的证据，但BDNF导致性别差异的过程仍未得到很好的理解。由于ASD症状的可变性和研究方法的变化，解释结果变得更加困难。除此之外，尚不清楚BDNF水平的增加是代表代偿过程还是实际上提供保护。在发育阶段监测BDNF表达的纵向研究，以及针对BDNF通路的性别特异性治疗方法，应该是未来研究的重点。因此，彻底了解BDNF如何防止ASD中的性别差异，可能为旨在降低ASD风险的创新策略铺平道路。在此背景下，本文回顾了目前的研究，强调性别差异、BDNF和ASD发病率之间的复杂关系。

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引用次数: 0

A critical role for the fascin family of actin bundling proteins in axon development, brain wiring and function 肌动蛋白束蛋白家族在轴突发育、大脑布线和功能中的关键作用

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-06-17 DOI: 10.1016/j.mcn.2025.104027

Katherine R. Hardin , Arjolyn B. Penas , Shuristeen Joubert , Changtian Ye , Kenneth R. Myers , James Q. Zheng

Actin-based cell motility drives many neurodevelopmental events including guided axonal growth. Fascin is a major family of F-actin bundling proteins, but its role in axon development in vivo and brain wiring remains unclear. Here, we report that fascin is required for axon development, brain wiring and function. We show that fascin is enriched in the motile filopodia of axonal growth cones and its inhibition impairs axonal extension and branching of hippocampal neurons in culture. We next provide evidence that fascin is essential for axon development and brain wiring in vivo using Drosophila melanogaster as a model. Drosophila expresses a single ortholog of mammalian fascin called Singed (Sn), which is expressed in the mushroom body (MB) of the central nervous system. Loss of Sn causes severe MB disruption, marked by α- and β-lobe defects indicative of altered axonal guidance. Sn-null flies also exhibit defective sensorimotor behaviors as assessed by the negative geotaxis assay. MB-specific expression of Sn in Sn-null flies rescues MB structure and sensorimotor deficits, indicating that Sn functions autonomously in MB neurons. Together, our data from primary neuronal culture and in vivo models highlight a critical role for fascin in brain development and function.

肌动蛋白为基础的细胞运动驱动许多神经发育事件，包括引导轴突生长。筋膜蛋白是f -肌动蛋白捆绑蛋白的一个主要家族，但其在体内轴突发育和大脑布线中的作用尚不清楚。在这里，我们报道了束状蛋白是轴突发育、大脑连接和功能所必需的。我们发现，束蛋白在轴突生长锥的运动丝状足中富集，其抑制作用损害了培养海马神经元的轴突延伸和分支。接下来，我们以黑腹果蝇为模型提供证据，证明束状蛋白对轴突发育和大脑连接至关重要。果蝇表达一种叫做Singed （Sn）的哺乳动物筋膜蛋白同源物，它在中枢神经系统的蘑菇体（MB）中表达。Sn的丢失导致严重的MB破坏，其特征是α-和β-叶缺陷，表明轴突导向改变。Sn-null果蝇也表现出缺陷的感觉运动行为，通过负地向性试验进行评估。在Sn缺失的果蝇中，Sn的MB特异性表达可修复MB结构和感觉运动缺陷，表明Sn在MB神经元中自主起作用。总之，我们从原代神经元培养和体内模型得到的数据强调了筋膜蛋白在大脑发育和功能中的关键作用。

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引用次数: 0

Multiple models of TBI in Drosophila yield common and unique genetic, physiological, behavioral outcomes 多种模型的TBI在果蝇产生共同的和独特的遗传，生理，行为结果

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-06-08 DOI: 10.1016/j.mcn.2025.104024

Seanna E. Kelly , Rebecca Delventhal , Annika F. Barber

Traumatic brain injury is a significant public health problem, but the complex pathology of TBI has posed a barrier to a molecular understanding of the root causes of post-TBI sequelae. Fruit fly models of TBI offer opportunities to conduct high throughput screens for genes affecting multiple outcomes of TBI. This review provides a primer on fly traumatic injury paradigms, a summary of findings made in fly TBI models, and recommendations for future areas of TBI research amenable to the fly model. Using the whole-animal and head-specific TBI paradigms available in Drosophila, researchers have identified changes in acute mortality and median lifespan, reduction in locomotor function, immune activation, remodeling of metabolic functions and sleep, and acceleration of neurodegenerative phenotypes. Fly TBI models also show effects of age, diet, and sex on injury outcomes. Drosophila genetic tools offer unique advantages for high throughput screening, and fly screens have identified genes that affect acute mortality after injury. Further standardization of fly TBI paradigms will advance the field and allow discovery of genes and biochemical pathways that affect TBI outcomes across species and accelerate the development of evidence-based treatments for TBI survivors.

创伤性脑损伤是一个重大的公共卫生问题，但创伤性脑损伤的复杂病理对了解创伤后后遗症的分子根源构成了障碍。TBI的果蝇模型为高通量筛选影响TBI多种结果的基因提供了机会。本文综述了蝇类创伤性损伤的研究范式，综述了蝇类创伤性脑损伤模型的研究成果，并对未来适用于蝇类创伤性脑损伤模型的研究领域提出了建议。利用果蝇的全动物和头部特异性TBI模型，研究人员已经确定了急性死亡率和中位寿命的变化，运动功能的减少，免疫激活，代谢功能和睡眠的重塑，以及神经退行性表型的加速。苍蝇TBI模型也显示了年龄、饮食和性别对损伤结果的影响。果蝇遗传工具为高通量筛选提供了独特的优势，苍蝇筛选已经确定了影响损伤后急性死亡率的基因。苍蝇TBI范式的进一步标准化将推动该领域的发展，并允许发现影响跨物种TBI结果的基因和生化途径，并加速TBI幸存者循证治疗的发展。

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引用次数: 0

Rethinking Parkinson's: The role of proteostasis networks and autophagy in disease progression 重新思考帕金森病：蛋白质平衡网络和自噬在疾病进展中的作用。

IF 2.6 3区医学 Q3 NEUROSCIENCES

Molecular and Cellular Neuroscience

Pub Date : 2025-06-07 DOI: 10.1016/j.mcn.2025.104023

Akhil Sharma, Ashi Mannan, Thakur Gurjeet Singh

Protein dyshomeostasis is identified as the hallmark of many age-related NDDs including Parkinson's disease (PD). PD is a progressive neurodegenerative disorder (NDD) characterized by the accumulation of misfolded proteins, particularly α-synuclein (α-syn) leading to formation of Lewy bodies and cause degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Disruption of the cell's normal protein balance, which occurs when cells experience stress, plays a key role in causing the formation of harmful protein clumps. Functional proteostasis relies on coordinated mechanisms involving posttranslational modifications (PTMs), molecular chaperones, the unfolded protein response (UPR), the ubiquitin-proteasome system (UPS), and the autophagy-lysosome pathway (ALP). These networks maintain proper synthesis, folding, confirmation and degradation of protein such as α-syn protein in PD. These approaches include enhancing lysosomal function, promoting autophagy and modulating the unfolded protein response. Understanding the complex interactions between these pathways is essential for developing effective treatments. This review synthesizes current knowledge of various genes and molecular mechanisms underlying proteostasis disruption in PD and evaluates emerging therapeutic strategies that target multiple genes and pathways simultaneously. The finding highlights the potential of integrated approaches to restore protein homeostasis and prevent neurodegeneration, offering new directions for PD treatment development.

蛋白质失衡被认为是许多与年龄相关的ndd的标志，包括帕金森病（PD）。PD是一种进行性神经退行性疾病（NDD），其特征是错误折叠蛋白，特别是α-突触核蛋白（α-syn）的积累导致路易小体的形成，并导致黑质致密部（SNpc）多巴胺能神经元的变性。当细胞受到压力时，细胞正常的蛋白质平衡就会被破坏，这在导致有害蛋白质团块的形成中起着关键作用。功能性蛋白质静止依赖于包括翻译后修饰（PTMs）、分子伴侣、未折叠蛋白反应（UPR）、泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP）在内的协调机制。这些网络维持PD中α-syn蛋白等蛋白质的正常合成、折叠、确认和降解。这些方法包括增强溶酶体功能，促进自噬和调节未折叠蛋白反应。了解这些途径之间复杂的相互作用对于开发有效的治疗方法至关重要。这篇综述综合了目前关于PD中蛋白质平衡破坏的各种基因和分子机制的知识，并评估了同时针对多个基因和途径的新兴治疗策略。这一发现突出了综合方法在恢复蛋白质稳态和预防神经退行性变方面的潜力，为PD治疗的发展提供了新的方向。

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