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The GFAP proteoform puzzle: How to advance GFAP as a fluid biomarker in neurological diseases GFAP 蛋白形态之谜:如何推动 GFAP 成为神经系统疾病的体液生物标记物
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1111/jnc.16226
Dea Gogishvili, Madison I. J. Honey, Inge M. W. Verberk, Lisa Vermunt, Elly M. Hol, Charlotte E. Teunissen, Sanne Abeln
Glial fibrillary acidic protein (GFAP) is a well‐established biomarker of reactive astrogliosis in the central nervous system because of its elevated levels following brain injury and various neurological disorders. The advent of ultra‐sensitive methods for measuring low‐abundant proteins has significantly enhanced our understanding of GFAP levels in the serum or plasma of patients with diverse neurological diseases. Clinical studies have demonstrated that GFAP holds promise both as a diagnostic and prognostic biomarker, including but not limited to individuals with Alzheimer's disease. GFAP exhibits diverse forms and structures, herein referred to as its proteoform complexity, encompassing conformational dynamics, isoforms and post‐translational modifications (PTMs). In this review, we explore how the proteoform complexity of GFAP influences its detection, which may affect the differential diagnostic performance of GFAP in different biological fluids and can provide valuable insights into underlying biological processes. Additionally, proteoforms are often disease‐specific, and our review provides suggestions and highlights areas to focus on for the development of new assays for measuring GFAP, including isoforms, PTMs, discharge mechanisms, breakdown products, higher‐order species and interacting partners. By addressing the knowledge gaps highlighted in this review, we aim to support the clinical translation and interpretation of GFAP in both CSF and blood and the development of reliable, reproducible and specific prognostic and diagnostic tests. To enhance disease pathology comprehension and optimise GFAP as a biomarker, a thorough understanding of detected proteoforms in biofluids is essential.image
胶质纤维酸性蛋白(GFAP)是中枢神经系统中反应性星形胶质细胞增生的一种公认的生物标志物,因为它在脑损伤和各种神经系统疾病后水平升高。超灵敏低富集蛋白测量方法的出现大大提高了我们对各种神经系统疾病患者血清或血浆中 GFAP 水平的了解。临床研究表明,GFAP 有望成为诊断和预后的生物标志物,包括但不限于阿尔茨海默氏症患者。GFAP 表现出多种形式和结构,这里称为其蛋白形式的复杂性,包括构象动态、同工酶和翻译后修饰 (PTM)。在这篇综述中,我们探讨了 GFAP 蛋白形态的复杂性如何影响其检测,这可能会影响 GFAP 在不同生物液体中的不同诊断性能,并能为潜在的生物过程提供有价值的见解。此外,蛋白形态通常具有疾病特异性,我们的综述为开发新的 GFAP 检测方法提供了建议,并强调了应重点关注的领域,包括同工酶、PTM、排出机制、分解产物、高阶物种和相互作用伙伴。通过解决本综述中强调的知识差距,我们旨在支持 CSF 和血液中 GFAP 的临床转化和解释,以及可靠、可重复和特异性预后和诊断测试的开发。为了提高对疾病病理的理解并优化作为生物标志物的 GFAP,透彻了解生物流体中检测到的蛋白形式至关重要。
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引用次数: 0
Compensatory changes after spinal cord injury in a remyelination deficient mouse model 再髓鞘化缺陷小鼠模型脊髓损伤后的补偿性变化
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-13 DOI: 10.1111/jnc.16220
S. B. Manesh, B. R. Kondiles, S. Wheeler, J. Liu, L. Zhang, C. Chernoff, G. J. Duncan, M. S. Ramer, W. Tetzlaff
The development of therapeutic strategies to reduce impairments following spinal cord injury (SCI) motivates an active area of research, because there are no effective therapies. One strategy is to address injury‐induced demyelination of spared axons by promoting endogenous or exogenous remyelination. However, previously, we showed that new myelin was not necessary to regain hindlimb stepping following moderate thoracic spinal cord contusion in 3‐month‐old mice. The present analysis investigated two potential mechanisms by which animals can re‐establish locomotion in the absence of remyelination: compensation through intact white matter and conduction through spared axons. We induced a severe contusion injury to reduce the spared white matter rim in the remyelination deficient model, with no differences in recovery between remyelination deficient animals and injured littermate controls. We investigated the nodal properties of the axons at the lesion and found that in the remyelination deficient model, axons express the Nav1.2 voltage‐gated sodium channel, a sub‐type not typically expressed at mature nodes of Ranvier. In a moderate contusion injury, conduction velocities through the lesions of remyelination deficient animals were similar to those in animals with the capacity to remyelinate after injury. Detailed gait analysis and kinematics reveal subtle differences between remyelination deficient animals and remyelination competent controls, but no worse deficits. It is possible that upregulation of Nav1.2 channels may contribute to establishing conduction through the lesion. This conduction could contribute to compensation and regained motor function in mouse models of SCI. Such compensatory mechanism may have implications for interpreting efficacy results for remyelinating interventions in mice and the development of therapies for improving recovery following SCI.image
由于目前还没有有效的疗法,因此开发治疗策略以减少脊髓损伤(SCI)后的损伤成为一个活跃的研究领域。其中一种策略是通过促进内源性或外源性再髓鞘化来解决损伤引起的幸免轴突脱髓鞘问题。然而,我们之前的研究表明,3 个月大的小鼠在中度胸脊髓挫伤后恢复后肢步态并不需要新的髓鞘。本分析研究了动物在没有髓鞘再形成的情况下重建运动的两种潜在机制:通过完整的白质进行补偿和通过幸免的轴突进行传导。我们诱导了严重的挫伤,以减少再髓鞘化缺陷模型中幸免的白质边缘,再髓鞘化缺陷动物与受伤的同窝对照组在恢复方面没有差异。我们研究了病变处轴突的结节特性,发现在再髓鞘化缺陷模型中,轴突表达Nav1.2电压门控钠通道,这种亚型通常不在成熟的Ranvier结节中表达。在中度挫伤中,通过髓鞘再形成缺陷动物病变部位的传导速度与受伤后具有髓鞘再形成能力的动物相似。详细的步态分析和运动学研究显示,再髓鞘化缺陷动物与有再髓鞘化能力的对照组之间存在细微差别,但没有更严重的缺陷。Nav1.2通道的上调可能有助于通过病变建立传导。这种传导可能有助于脊髓损伤小鼠模型的代偿和运动功能的恢复。这种代偿机制可能对解释小鼠再髓鞘化干预的疗效结果和开发改善 SCI 后恢复的疗法有影响。
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引用次数: 0
Linking activation of synaptic NMDA receptors‐induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid‐beta peptide 将激活突触 NMDA 受体诱导的 CREB 信号与大脑皮层神经元短暂暴露于寡聚淀粉样蛋白-β肽联系起来
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-12 DOI: 10.1111/jnc.16222
I. Luísa Ferreira, Daniela Marinho, Valéria de Rosa, Bárbara Castanheira, Zongwei Fang, Gladys L. Caldeira, Sandra I. Mota, A. Cristina Rego
Amyloid‐beta peptide oligomers (AβO) have been considered “primum movens” for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AβO have not been clearly defined. Synaptic (Syn) N‐methyl‐d‐aspartate receptors (NMDAR) are known to activate cAMP response element‐binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+i). Thus, in this work, we analyze acute/early and long‐term AβO‐mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR‐mediated Ca2+ influx. Data also demonstrate that AβO long‐term (24 h) exposure compromises synaptic function related to Ca2+‐dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AβO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.image
淀粉样β肽寡聚体(AβO)被认为是阿尔茨海默病(AD)中最终导致选择性神经元死亡的一系列事件的 "首要动因"。然而,AβO 引发的最初事件尚未得到明确界定。已知突触(Syn)N-甲基-d-天冬氨酸受体(NMDAR)可激活cAMP反应元件结合蛋白(CREB),CREB是一种转录因子,参与细胞存活、记忆形成和突触可塑性相关基因的表达,而突触外(ESyn)NMDAR的激活则与兴奋毒性事件有关。在 AD 脑中,CREB 磷酸化/激活被证明发生了改变,同时细胞内 Ca2+ (Ca2+i) 的平衡失调。因此,在这项研究中,我们分析了急性/早期和长期 AβO 介导的 CREB 激活变化,这些变化涉及成熟大鼠皮质神经元中的 Syn 或 ESyn NMDARs。我们的研究结果表明,急性 AβO 暴露会产生磷酸化 CREB 的早期增加,反映了 CREB 的活性,这一过程是通过 Syn NMDAR 介导的 Ca2+ 流入发生的。数据还表明,长期(24 小时)暴露于 AβO 会损害与 Ca2+ 依赖性 CREB 磷酸化/激活、核 CREB 水平及相关靶基因(即 Bdnf、Gadd45γ 和 Btg2)有关的突触功能。数据表明,早期或长期暴露于 AβO 后,成熟的大脑皮层神经元会通过激活 CREB 信号通路产生双重效应,这与 Syn NMDARs 的激活有关。
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引用次数: 0
From BBB to PPP: Bioenergetic requirements and challenges for oligodendrocytes in health and disease 从 BBB 到 PPP:少突胶质细胞在健康和疾病中的生物能需求与挑战
IF 4.7 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1111/jnc.16219
Milton Guilherme Forestieri Fernandes, Florian Pernin, Jack P. Antel, Timothy E. Kennedy
Mature myelinating oligodendrocytes, the cells that produce the myelin sheath that insulates axons in the central nervous system, have distinct energetic and metabolic requirements compared to neurons. Neurons require substantial energy to execute action potentials, while the energy needs of oligodendrocytes are directed toward building the lipid‐rich components of myelin and supporting neuronal metabolism by transferring glycolytic products to axons as additional fuel. The utilization of energy metabolites in the brain parenchyma is tightly regulated to meet the needs of different cell types. Disruption of the supply of metabolites can lead to stress and oligodendrocyte injury, contributing to various neurological disorders, including some demyelinating diseases. Understanding the physiological properties, structures, and mechanisms involved in oligodendrocyte energy metabolism, as well as the relationship between oligodendrocytes and neighboring cells, is crucial to investigate the underlying pathophysiology caused by metabolic impairment in these disorders. In this review, we describe the particular physiological properties of oligodendrocyte energy metabolism and the response of oligodendrocytes to metabolic stress. We delineate the relationship between oligodendrocytes and other cells in the context of the neurovascular unit, and the regulation of metabolite supply according to energetic needs. We focus on the specific bioenergetic requirements of oligodendrocytes and address the disruption of metabolic energy in demyelinating diseases. We encourage further studies to increase understanding of the significance of metabolic stress on oligodendrocyte injury, to support the development of novel therapeutic approaches for the treatment of demyelinating diseases.image
成熟的髓鞘化少突胶质细胞是产生髓鞘的细胞,髓鞘在中枢神经系统中对轴突起绝缘作用,与神经元相比,少突胶质细胞对能量和新陈代谢的需求各不相同。神经元需要大量能量来执行动作电位,而少突胶质细胞的能量需求则用于构建髓鞘中富含脂质的成分,并通过将糖酵解产物转移到轴突作为额外燃料来支持神经元的新陈代谢。脑实质中能量代谢产物的利用受到严格调控,以满足不同类型细胞的需要。代谢产物供应的中断会导致压力和少突胶质细胞损伤,从而引发各种神经系统疾病,包括一些脱髓鞘疾病。了解少突胶质细胞能量代谢所涉及的生理特性、结构和机制,以及少突胶质细胞与邻近细胞之间的关系,对于研究这些疾病中代谢障碍所导致的潜在病理生理学至关重要。在这篇综述中,我们描述了少突胶质细胞能量代谢的特殊生理特性以及少突胶质细胞对代谢压力的反应。我们描述了少突胶质细胞与神经血管单元中其他细胞之间的关系,以及根据能量需求对代谢物供应的调节。我们重点研究了少突胶质细胞对生物能的特殊需求,并探讨了脱髓鞘疾病对代谢能的破坏。我们鼓励开展进一步研究,以加深了解代谢压力对少突胶质细胞损伤的重要意义,从而为开发治疗脱髓鞘疾病的新型疗法提供支持。
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引用次数: 0
Increased forebrain EAAT3 expression confers resilience to chronic stress. 增加前脑EAAT3的表达可增强对慢性压力的适应能力
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-08 DOI: 10.1111/jnc.16216
Nicolás M Ardiles, Vissente Tapia-Cuevas, Sebastián F Estay, Alejandro Alcaino, Victoria B Velásquez, Ramón Sotomayor-Zárate, Andrés E Chávez, Pablo R Moya

Depression is a disabling and highly prevalent psychiatric illness. Multiple studies have linked glutamatergic dysfunction with the pathophysiology of depression, but the exact alterations in the glutamatergic system that contribute to depressive-like behaviors are not fully understood. Recent evidence suggests that a decreased level in neuronal glutamate transporter (EAAT3), known to control glutamate levels and limit the activation of glutamate receptors at synaptic sites, may contribute to the manifestation of a depressive phenotype. Here, we tested the possibility that increased EAAT3 expression at excitatory synapses could reduce the susceptibility of mice to develop depressive-like behaviors when challenged to a 5-week unpredictable chronic mild stress (UCMS) protocol. Mice overexpressing EAAT3 in the forebrain (EAAT3glo/CMKII) and control littermates (EAAT3glo) were assessed for depressive-like behaviors and long-term memory performance after being subjected to UCMS conditions. We found that, after UCMS, EAAT3glo/CMKII mice did not exhibit depressive-like behaviors or memory alterations observed in control mice. Moreover, we found that EAAT3glo/CMKII mice did not show alterations in phasic dopamine release in the nucleus accumbens neither in long-term synaptic plasticity in the CA1 region of the hippocampus after UCMS, as observed in control littermates. Altogether these results suggest that forebrain EAAT3 overexpression may be related to a resilient phenotype, both at behavioral and functional level, to the deleterious effect of chronic stress, highlighting the importance of neuronal EAAT3 in the pathophysiology of depressive-like behaviors.

抑郁症是一种致残性、高发病率的精神疾病。多项研究表明,谷氨酸能功能障碍与抑郁症的病理生理学有关,但导致抑郁样行为的谷氨酸能系统的确切改变尚不完全清楚。最近的证据表明,神经元谷氨酸转运体(EAAT3)水平的降低可能会导致抑郁表型的表现,已知EAAT3能控制谷氨酸水平并限制突触部位谷氨酸受体的激活。在这里,我们测试了在兴奋性突触处增加 EAAT3 表达是否能降低小鼠在接受为期 5 周的不可预测慢性温和应激(UCMS)方案挑战时产生抑郁样行为的易感性。我们对前脑过表达 EAAT3 的小鼠(EAAT3glo/CMKII)和对照组小鼠(EAAT3glo)进行了抑郁样行为和长期记忆表现的评估。我们发现,在 UCMS 之后,EAAT3glo/CMKII 小鼠没有表现出对照组小鼠所观察到的抑郁样行为或记忆改变。此外,我们还发现,EAAT3glo/CMKII 小鼠在 UCMS 后并没有表现出与对照组同窝小鼠一样的凹凸核多巴胺阶段性释放的改变,也没有表现出海马 CA1 区长期突触可塑性的改变。总之,这些结果表明,前脑 EAAT3 的过度表达可能与一种在行为和功能水平上对慢性应激的有害影响具有恢复力的表型有关,突出了神经元 EAAT3 在抑郁样行为的病理生理学中的重要性。
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引用次数: 0
Visualization of myelin-forming oligodendrocytes in the adult mouse brain. 成年小鼠大脑中髓鞘形成少突胶质细胞的可视化。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1111/jnc.16218
Kiichi Yokoyama, Yuichi Hiraoka, Yoshifumi Abe, Kenji F Tanaka

Oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs) is considered to result in two populations: premyelinating and myelinating OLs. Recent single-cell RNA sequence data subdivided these populations into newly formed (NFOLs), myelin-forming (MFOLs), and mature (MOLs) oligodendrocytes. However, which newly proposed population corresponds to premyelinating or myelinating OLs is unknown. We focused on the NFOL-specific long non-coding oligodendrocyte 1 gene (LncOL1) and sought to label NFOLs under the control of the LncOL1 promoter using a tetracycline-controllable gene induction system. We demonstrated that LncOL1 was expressed by premyelinating OLs and that the MFOL-specific gene, Ctps, was not, indicating that NFOLs correspond to premyelinating OLs and that MFOLs and MOLs correspond to myelinating OLs. We then generated a LncOL1-tTA mouse in which a tetracycline transactivator (tTA) cassette was inserted downstream from the LncOL1 transcription initiation site. By crossing the LncOL1-tTA mice with tetO reporter mice, we generated LncOL1-tTA::tetO-yellow fluorescent protein (YFP) double-transgenic (LncOL1-YFP) mice. Although LncOL1 is non-coding, YFP was detected in LncOL1-YFP mice, indicating successful tTA translation. Unexpectedly, we found that the morphology of LncOL1-tTA-driven YFP+ cells was distinct from that of LncOL1+ premyelinating OLs and that the labeled cells instead appeared as myelinating OLs. We demonstrated from their RNA expression that YFP-labeled OLs were MFOLs, but not MOLs. Using the unique property of delayed YFP induction, we sought to determine whether MFOLs are constantly supplied from OPCs and differentiate into MOLs, or whether MFOLs pause their differentiation and sustain this stage in the adult brain. To achieve this objective, we irradiated adult LncOL1-YFP brains with X-rays to deplete dividing OPCs and their progeny. The irradiation extinguished YFP-labeled OLs, indicating that adult OPCs differentiated into MOLs during a single period. We established a new transgenic mouse line that genetically labels MFOLs, providing a reliable tool for investigating the dynamics of adult oligodendrogenesis.

少突胶质细胞(OL)从少突胶质细胞前体细胞(OPCs)分化而来,被认为会产生两个群体:前髓鞘化少突胶质细胞和髓鞘化少突胶质细胞。最近的单细胞 RNA 序列数据将这些群体细分为新形成(NFOLs)、髓鞘形成(MFOLs)和成熟(MOLs)少突胶质细胞。然而,哪个新提出的群体对应于髓鞘化前或髓鞘化的少突胶质细胞尚不清楚。我们重点研究了NFOL特异性长非编码少突胶质细胞1基因(LncOL1),并试图利用四环素可控基因诱导系统对LncOL1启动子控制下的NFOL进行标记。我们证明髓鞘前OLs表达LncOL1,而MFOL特异性基因Ctps不表达,这表明NFOLs对应于髓鞘前OLs,而MFOLs和MOLs对应于髓鞘OLs。随后,我们生成了一种LncOL1-tTA小鼠,其中在LncOL1转录起始位点下游插入了一个四环素转录激活剂(tTA)盒。通过将 LncOL1-tTA 小鼠与 tetO 报告小鼠杂交,我们产生了 LncOL1-tTA::tetO-黄色荧光蛋白(YFP)双转基因(LncOL1-YFP)小鼠。虽然 LncOL1 是非编码,但在 LncOL1-YFP 小鼠中检测到了 YFP,这表明 tTA 翻译成功。意想不到的是,我们发现 LncOL1-tTA 驱动的 YFP+ 细胞的形态与 LncOL1+ 髓鞘化前 OL 的形态不同,标记的细胞显示为髓鞘化 OL。我们通过其 RNA 表达证明,YFP 标记的 OL 是 MFOL,而不是 MOL。利用延迟诱导 YFP 的独特特性,我们试图确定 MFOLs 是否不断从 OPCs 中获得供应并分化为 MOLs,或者 MFOLs 是否暂停分化并在成人大脑中维持这一阶段。为了实现这一目标,我们用 X 射线照射 LncOL1-YFP 成年人大脑,以消耗正在分裂的 OPCs 及其后代。照射后,YFP标记的OL熄灭,表明成年OPC在一个时期内分化为MOL。我们建立了一个新的转基因小鼠品系,该品系可对MFOLs进行基因标记,为研究成体少突发生的动态提供了可靠的工具。
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引用次数: 0
Relaxin family peptide receptor 3 (RXFP3) expressing cells in the zona incerta/lateral hypothalamus augment behavioural arousal. 下丘脑内侧带/外侧的松弛素家族肽受体3(RXFP3)表达细胞可增强行为唤醒。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1111/jnc.16217
Brandon K Richards, Sarah S Ch'ng, Ariel B Simon, Terence Y Pang, Jee Hyun Kim, Andrew J Lawrence, Christina J Perry

Fear-related psychopathologies, such as post-traumatic stress disorder, are linked to dysfunction in neural circuits that govern fear memory and arousal. The lateral hypothalamus (LH) and zona incerta (ZI) regulate fear, but our understanding of the precise neural circuits and cell types involved remains limited. Here, we examined the role of relaxin family peptide receptor 3 (RXFP3) expressing cells in the LH/ZI in conditioned fear expression and general arousal in male RXFP3-Cre mice. We found that LH/ZI RXFP3+ (LH/ZIRXFP3) cells projected strongly to fear learning, stress, and arousal centres, notably, the periaqueductal grey, lateral habenula, and nucleus reuniens. These cells do not express hypocretin/orexin or melanin-concentrating hormone but display putative efferent connectivity with LH hypocretin/orexin+ neurons and dopaminergic A13 cells. Following Pavlovian fear conditioning, chemogenetically activating LH/ZIRXFP3 cells reduced fear expression (freezing) overall but also induced jumping behaviour and increased locomotor activity. Therefore, the decreased freezing was more likely to reflect enhanced arousal rather than reduced fear. Indeed, stimulating these cells produced distinct patterns of coactivation between several motor, stress, and arousal regions, as measured by Fos expression. These results suggest that activating LH/ZIRXFP3 cells generates brain-wide activation patterns that augment behavioural arousal.

与恐惧有关的精神病理学,如创伤后应激障碍,与支配恐惧记忆和唤醒的神经回路功能障碍有关。外侧下丘脑(LH)和内侧下丘脑(ZI)调节恐惧,但我们对其中涉及的精确神经回路和细胞类型的了解仍然有限。在这里,我们研究了雄性 RXFP3-Cre 小鼠 LH/ZI 中表达弛缓素家族肽受体 3(RXFP3)的细胞在条件性恐惧表达和一般唤醒中的作用。我们发现,LH/ZI RXFP3+(LH/ZIRXFP3)细胞强烈投射到恐惧学习、应激和唤醒中枢,尤其是咽周灰质、外侧哈文脑和团圆核。这些细胞不表达视网膜下素/视网膜素或黑色素浓缩激素,但显示出与LH视网膜下素/视网膜素+神经元和多巴胺能A13细胞的传出连接。在巴甫洛夫恐惧条件反射后,化学激活 LH/ZIRXFP3 细胞可减少恐惧表达(冻结),但也可诱导跳跃行为和增加运动活动。因此,冻结的减少更有可能反映了唤醒的增强,而不是恐惧的减少。事实上,刺激这些细胞会在多个运动、应激和唤醒区域之间产生不同的共激活模式,这是由 Fos 表达所衡量的。这些结果表明,激活LH/ZIRXFP3细胞可产生全脑激活模式,从而增强行为唤醒。
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引用次数: 0
Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins. 淀粉样肽和其他生物毒素对线粒体膜的分隔作用。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1111/jnc.16213
Neville Vassallo

Mitochondria are essential organelles known to serve broad functions, including in cellular metabolism, calcium buffering, signaling pathways and the regulation of apoptotic cell death. Maintaining the integrity of the outer (OMM) and inner mitochondrial membranes (IMM) is vital for mitochondrial health. Cardiolipin (CL), a unique dimeric glycerophospholipid, is the signature lipid of energy-converting membranes. It plays a significant role in maintaining mitochondrial architecture and function, stabilizing protein complexes and facilitating efficient oxidative phosphorylation (OXPHOS) whilst regulating cytochrome c release from mitochondria. CL is especially enriched in the IMM and at sites of contact between the OMM and IMM. Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid-β, tau and α-synuclein, which form metastable toxic oligomeric species that interact with biological membranes. Electrophysiological studies have shown that these oligomers form ion-conducting nanopores in membranes mimicking the IMM's phospholipid composition. Poration of mitochondrial membranes disrupts the ionic balance, causing osmotic swelling, loss of the voltage potential across the IMM, release of pro-apoptogenic factors, and leads to cell death. The interaction between CL and amyloid oligomers appears to favour their membrane insertion and pore formation, directly implicating CL in amyloid toxicity. Additionally, pore formation in mitochondrial membranes is not limited to amyloid proteins and peptides; other biological peptides, as diverse as the pro-apoptotic Bcl-2 family members, gasdermin proteins, cobra venom cardiotoxins and bacterial pathogenic toxins, have all been described to punch holes in mitochondria, contributing to cell death processes. Collectively, these findings underscore the vulnerability of mitochondria and the involvement of CL in various pathogenic mechanisms, emphasizing the need for further research on targeting CL-amyloid interactions to mitigate mitochondrial dysfunction.

线粒体是重要的细胞器,具有广泛的功能,包括细胞代谢、钙缓冲、信号通路和细胞凋亡调控。保持线粒体外膜(OMM)和内膜(IMM)的完整性对线粒体的健康至关重要。心磷脂(CL)是一种独特的二聚甘油磷脂,是能量转换膜的标志性脂质。它在维持线粒体结构和功能、稳定蛋白质复合物、促进高效氧化磷酸化(OXPHOS)以及调节线粒体释放细胞色素 c 方面发挥着重要作用。CL尤其富集在线粒体内膜和线粒体外膜与线粒体内膜的接触部位。阿尔茨海默氏症和帕金森氏症等蛋白质错误折叠疾病涉及淀粉样蛋白-β、tau 和 α-突触核蛋白等淀粉样蛋白肽,这些肽会形成可转移的有毒低聚物,与生物膜相互作用。电生理学研究表明,这些低聚物会在模仿 IMM 磷脂成分的膜上形成离子传导纳米孔。线粒体膜上的孔破坏了离子平衡,导致渗透膨胀、跨线粒体膜的电压电位下降、促凋亡因子释放并导致细胞死亡。CL 与淀粉样蛋白寡聚体之间的相互作用似乎有利于它们的膜插入和孔隙形成,这直接表明 CL 与淀粉样蛋白的毒性有关。此外,线粒体膜孔隙的形成并不局限于淀粉样蛋白和肽,其他生物肽,如促凋亡的 Bcl-2 家族成员、gasdermin 蛋白、眼镜蛇毒心脏毒素和细菌致病毒素,都被描述为在线粒体上打孔,导致细胞死亡的过程。总之,这些发现强调了线粒体的脆弱性以及CL在各种致病机制中的参与,强调了进一步研究针对CL-淀粉样蛋白相互作用以缓解线粒体功能障碍的必要性。
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引用次数: 0
Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice. 曲利卢唑可挽救 3xTg-AD 小鼠的谷氨酸能缺陷、淀粉样蛋白和 tau 病理学以及突触和记忆损伤。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-30 DOI: 10.1111/jnc.16215
Jeremiah Pfitzer, Priyanka D Pinky, Savannah Perman, Emma Redmon, Luca Cmelak, Vishnu Suppiramaniam, Vladimir Coric, Irfan A Qureshi, Michael W Gramlich, Miranda N Reed

Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aβ) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aβ models, suggesting the changes in pool size may be due to Aβ and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer's disease.

阿尔茨海默病(AD)是一种神经退行性疾病,其临床症状与谷氨酸能突触的丧失密切相关。阿尔茨海默病晚期由于神经元缺失,谷氨酸水平明显下降,而在早期,谷氨酸的病理性积累和亢进会导致阿尔茨海默病的病理变化和认知功能障碍。越来越多的人认识到,突触前功能障碍,尤其是突触小泡(SV)的改变,在介导这种早期亢进中起着关键作用。在本研究中,我们试图确定同时表现出β-淀粉样蛋白(Aβ)和tau相关病理变化的3xTg小鼠AD模型是否会表现出与之前在淀粉样蛋白或tau模型中分别观察到的类似突触前变化。我们使用 3xTg 小鼠的海马培养物来确定突触前囊泡谷氨酸转运体(VGlut)和谷氨酸是否在突触水平增加,同时控制突触后活动。我们观察到,3xTg 海马培养物表现出与谷氨酸释放增加相关的 VGlut1 增加,这与之前在 tau 小鼠模型培养物中观察到的结果类似。然而,3xTg 培养物中 SV 池的大小也增加了,这是之前在 tau 小鼠模型中没有观察到的,但在 Aβ 模型中观察到了,这表明池大小的变化可能是由于 Aβ 而不是 tau 引起的。其次,我们试图确定使用谷氨酸调节剂利鲁唑的新型第三代三肽原药曲利鲁唑治疗是否能减少 VGlut1 和谷氨酸的释放,从而恢复 8 个月大的 3xTg 小鼠的认知障碍。使用曲利卢唑治疗可减少 VGlut1 的表达,降低谷氨酸的基础释放和诱发释放,并恢复 3xTg 小鼠的认知障碍。这些发现共同表明突触前改变是阿兹海默病的早期事件,是治疗干预的潜在靶点,这些结果支持了谷氨酸调节药物(如曲利卢唑)治疗阿兹海默病的前景。
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引用次数: 0
Clinical, molecular, physiologic, and therapeutic feature of patients with CHRNA4 and CHRNB2 deficiency: A systematic review. CHRNA4 和 CHRNB2 缺乏症患者的临床、分子、生理和治疗特征:系统综述。
IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-28 DOI: 10.1111/jnc.16200
Abbas Jalaiei, Mohammad Reza Asadi, Yousef Daneshmandpour, Maryam Rezazadeh, Soudeh Ghafouri-Fard

The α4β2 nAChRs are crucial ion channels that control neurotransmitter release and play a role in various physiologic and pathologic processes. CHRNA4 encodes the α4-nAChRs, while CHRNB2 encodes the β2-nAChRs. Recent studies have found different variants of α4β2-nAChRs in individuals with conditions such as AD, ADHD, ALS, PD, and brain abnormalities. We conducted a scoping review following a six-stage methodology structure and adhering to PRISMA guidelines. We systematically reviewed articles using relevant keywords up to October 2, 2023. In this summary, we cover the clinical symptoms reported, the genes and protein structure of CHRNA4 and CHRNB2, mutations in these genes, inheritance patterns, the functional impact of mutations and polymorphisms in CHRNA4 and CHRNB2, and the epidemiology of these diseases. Recent research indicates that nAChRs may play a significant role in neurodegenerative disorders, possibly impacting neuronal function through yet undiscovered regulatory pathways. Studying how nAChRs interact with disease-related aggregates in neurodegenerative conditions may lead to new treatment options for these disorders.

α4β2 nAChRs 是控制神经递质释放的重要离子通道,在各种生理和病理过程中发挥作用。CHRNA4 编码α4-nAChRs,而 CHRNB2 编码β2-nAChRs。最近的研究发现,在患有注意力缺失症(AD)、多动症(ADHD)、肌萎缩性脊髓侧索硬化症(ALS)、帕金森病(PD)和大脑异常等疾病的患者中,α4β2-nAChRs 存在不同的变体。我们按照六阶段方法结构并遵循 PRISMA 指南进行了范围界定综述。我们使用相关关键词对截至 2023 年 10 月 2 日的文章进行了系统综述。在本摘要中,我们介绍了所报道的临床症状、CHRNA4 和 CHRNB2 的基因和蛋白结构、这些基因的突变、遗传模式、CHRNA4 和 CHRNB2 的突变和多态性对功能的影响以及这些疾病的流行病学。最新研究表明,nAChRs 可能在神经退行性疾病中扮演重要角色,可能通过尚未发现的调节途径影响神经元功能。研究神经退行性疾病中的 nAChRs 如何与疾病相关的聚集体相互作用,可能会为这些疾病带来新的治疗方案。
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引用次数: 0
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Journal of Neurochemistry
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