Current Opinion in Neurobiology最新文献

英文中文

ALS-related proteinopathies: From TDP-43 to mitochondrial proteinopathies als相关蛋白病变：从TDP-43到线粒体蛋白病变

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2026-01-21 DOI: 10.1016/j.conb.2025.103163

Emmanuelle C. Genin , Véronique Paquis-Flucklinger

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons. ALS often overlaps clinically and pathologically with frontotemporal dementia (FTD), the second most common form of dementia. Like many neurodegenerative disorders, both ALS and FTD share a crucial pathological hallmark, the aggregation of misfolded proteins into insoluble inclusions in degenerating neurons. This process is referred to as proteinopathy. This review focuses on the proteinopathies associated with ALS, including aggregates of TDP-43, SOD1, FUS, and CHCHD10, which disrupt critical cellular processes such as RNA metabolism, mitochondrial function, and protein homeostasis. The review highlights to the identification of new types of mitochondrial and cytosolic aggregates linked to CHCHD10-related ALS. Although the precise pathological mechanisms remain to be fully elucidated, strategies aimed at restoring proteostasis and reducing protein aggregation may be promising therapeutic approaches for treating ALS, as they directly target fundamental pathogenic mechanisms.

肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元的进行性丧失。ALS通常在临床和病理上与额颞叶痴呆（FTD）重叠，额颞叶痴呆是第二常见的痴呆形式。像许多神经退行性疾病一样，ALS和FTD都有一个重要的病理特征，即在退化的神经元中错误折叠的蛋白质聚集成不溶性包涵体。这个过程被称为蛋白质病。这篇综述的重点是与ALS相关的蛋白质病变，包括TDP-43、SOD1、FUS和CHCHD10的聚集，它们会破坏关键的细胞过程，如RNA代谢、线粒体功能和蛋白质稳态。这篇综述的重点是鉴定与chchd10相关的ALS相关的新型线粒体和细胞质聚集体。虽然确切的病理机制仍有待完全阐明，但旨在恢复蛋白质平衡和减少蛋白质聚集的策略可能是治疗ALS的有希望的治疗方法，因为它们直接针对基本的致病机制。

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引用次数: 0

The challenges of experimental pharmacology in identifying novel treatments for Parkinson's disease 实验药理学在确定帕金森病新疗法中的挑战

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2026-01-21 DOI: 10.1016/j.conb.2025.103164

Margaux Teil , Philippe Huot

An important part of the field of experimental pharmacology encompasses the study of the effects of molecules in animals. In the case of Parkinson's disease (PD), animal models have played an invaluable role in refining our understanding of the disease, in characterizing the effect of new compounds on the illness, and in bringing new treatments to the clinic. Indeed, it is now hardly conceivable that a drug would be tested in humans if several parameters pertaining to safety, toxicology, efficacy, etc. had not previously been evaluated in animal models. Quite unfortunately, efficacy in experimental models of PD does not necessarily guarantee positive clinical outcomes. In this article, which primarily focusses on the past five years, we review drugs that entered clinical trials for the treatment of levodopa-induced dyskinesia, parkinsonism, disease modification, and had previously been assessed in animal models of PD. The drugs discussed are buspirone, JM-010, befiradol, mesdopetam, foliglurax, dipraglurant, tavapadon, prasinezumab, cinpanemab, nilotinib, minzasolmin, exenatide, NLY01, liraglutide, lixisenatide, and semaglutide. For each molecule, we examine how previous preclinical studies succeeded or failed in predicting efficacy in clinical trials and discuss possible ways to optimize animal-model design and selection to maximize the probability of translational success.

实验药理学领域的一个重要组成部分包括对分子在动物中的作用的研究。在帕金森病（PD）的案例中，动物模型在完善我们对疾病的理解，描述新化合物对疾病的影响以及将新的治疗方法引入临床方面发挥了宝贵的作用。事实上，如果一种药物之前没有在动物模型中进行过安全性、毒理学、有效性等方面的评估，那么现在很难想象这种药物会在人类身上进行测试。非常不幸的是，PD实验模型的疗效并不一定保证积极的临床结果。在这篇文章中，主要集中在过去的五年里，我们回顾了进入临床试验的药物，用于治疗左旋多巴诱导的运动障碍、帕金森病、疾病改变，以及之前在PD动物模型中进行的评估。所讨论的药物有丁吡酮、JM-010、贝非拉多、美塞哌坦、福莱格鲁、双普拉格朗、他伐巴东、普拉西单抗、辛帕那单抗、尼罗替尼、米沙索明、艾塞那肽、NLY01、利拉鲁肽、利西塞那肽和semaglutide。对于每个分子，我们检查了以前的临床前研究如何成功或失败地预测临床试验中的疗效，并讨论了优化动物模型设计和选择的可能方法，以最大限度地提高转化成功的可能性。

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引用次数: 0

The Enterarchon: An ancient visceral brain 肠执政官：一个古老的内脏大脑

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2026-01-14 DOI: 10.1016/j.conb.2025.103162

Bryon Silva , Mael Lemoine , Michael Rera , Dafni Hadjieconomou

The gastrointestinal (GI) tract is innervated by intrinsic neurites and extrinsic pathways linking it bidirectionally to the central nervous system. These circuits regulate digestion, metabolism, and homeostasis across metazoans. Comparative evidence from early-diverging animals to Drosophila and vertebrates suggests gut-embedded circuits arose on an epithelial/peptidergic scaffold and evolved in parallel across lineages, coordinating motility and secretion before centralised brains emerged. While vertebrates offer detailed molecular atlases of enteric nervous system (ENS) cell types, flies allow linking molecular identity with physiological function at cellular resolution. We highlight how the intestine-ENS axis integrates endocrine and immune signals and undergoes remodelling along three axes: sex as a constitutive dimorphism, reproduction as a reversible plasticity, and ageing as a biphasic trajectory. This comparative view challenges brain-centric models of systemic regulation. We propose instead that the intestine, through its neuronal, epithelial, and immune components, acts as an Enterarchon: an ancient visceral brain shaping organismal homeostasis.

胃肠道受内在神经突和外在神经通路的支配，它们与中枢神经系统双向相连。这些回路调节着后生动物的消化、代谢和体内平衡。从早期分化的动物到果蝇和脊椎动物的比较证据表明，肠道内嵌入回路是在上皮/肽能支架上产生的，并在谱系中平行进化，在集中式大脑出现之前协调运动和分泌。虽然脊椎动物提供肠神经系统（ENS）细胞类型的详细分子图谱，但苍蝇允许在细胞分辨率上将分子身份与生理功能联系起来。我们强调肠道-神经系统轴如何整合内分泌和免疫信号，并沿着三个轴进行重塑：性作为一个构成的二态性，生殖作为一个可逆的可塑性，衰老作为一个双相轨迹。这种比较观点挑战了以大脑为中心的系统调节模型。相反，我们提出肠道通过其神经元、上皮和免疫成分，充当肠执政官：一种古老的内脏大脑，塑造有机体的内稳态。

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引用次数: 0

Sexually dimorphic neural circuits underlying mating behaviors: Insights from worms, flies, and mice 交配行为背后的两性二态神经回路：来自蠕虫、苍蝇和老鼠的见解。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-23 DOI: 10.1016/j.conb.2025.103151

Xia-Jing Tong , Fei Wang , Xiaohong Xu

In sexually reproducing animals, males and females are biologically specialized to produce sperm or eggs, which must unite through mating to ensure successful reproduction. To facilitate this, each sex displays sex-specific, often stereotyped, mating behaviors orchestrated by neural circuits that undergo sexual differentiation during development. Extensive anatomical mapping and functional dissection in genetically tractable model organisms, including Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus, have revealed many sexually dimorphic neuronal populations and neural circuits. While previous reviews have offered broad cross-species comparisons of such sex differences in the nervous system [1,2], here we take a more focused approach. We specifically examine the neural substrates underlying mating behaviors across these three species, aiming to highlight shared principles in circuit architecture and to advance the emerging concept of connectome sex.

在有性繁殖的动物中，雄性和雌性在生物学上是专门产生精子或卵子的，它们必须通过交配结合才能确保成功繁殖。为了促进这一点，每一种性别都表现出性别特异性的、通常是刻板的、由发育过程中经历性别分化的神经回路精心安排的交配行为。在遗传易学的模式生物中，包括秀丽隐杆线虫、黑腹果蝇和小家鼠，广泛的解剖图谱和功能解剖揭示了许多两性二态的神经元群体和神经回路。虽然以前的评论已经提供了神经系统性别差异的跨物种比较[1,2]，但在这里我们采取了更集中的方法。我们特别研究了这三个物种交配行为背后的神经基质，旨在强调电路结构的共同原则，并推进连接体性别的新兴概念。

引用次数: 0

Development of the social behavior network 社会行为网络的发展

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-20 DOI: 10.1016/j.conb.2025.103159

Nolwenn Adam, Jessica Tollkuhn

Social behaviors are crucial for reproductive success and survival. In vertebrates, these behaviors are sexually dimorphic due to distinct hormonal environments in development and adulthood. The underlying neural pathways, collectively known as the social behavior network (SBN), consist of interconnected regions exhibiting sex-variable genomic, anatomical, and functional characteristics. While the structure and function of the adult SBN is increasingly well described, its embryonic origins and development remain poorly understood. All neural networks undergo extensive genomic and functional changes during development, but a unique feature of the SBN is its sensitivity to gonadal hormones. Transient developmental hormone signaling ultimately results in anatomic SBN sexual dimorphism and sex-variable behavioral repertoires. However, the precise mechanisms linking early life hormone signaling to the establishment of neural sex differences remain elusive. This review highlights recent findings on SBN development spanning embryonic timepoints to puberty, offering valuable perspectives to address this critical topic.

社会行为对繁殖成功和生存至关重要。在脊椎动物中，由于发育和成年时不同的激素环境，这些行为是两性二态的。潜在的神经通路，统称为社会行为网络（SBN），由相互连接的区域组成，表现出性别可变的基因组、解剖学和功能特征。虽然成人SBN的结构和功能越来越被很好地描述，但其胚胎起源和发育仍然知之甚少。所有神经网络在发育过程中都经历了广泛的基因组和功能变化，但SBN的一个独特特征是它对性腺激素的敏感性。短暂的发育激素信号最终导致解剖上的SBN性二态性和性别可变的行为表现。然而，将生命早期激素信号与神经性别差异的建立联系起来的确切机制仍然难以捉摸。这篇综述强调了从胚胎到青春期的SBN发育的最新发现，为解决这一关键问题提供了有价值的观点。

引用次数: 0

Gene therapy for Parkinson’s disease—Ample room for optimism 帕金森氏症的基因疗法——有足够的乐观空间

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-19 DOI: 10.1016/j.conb.2025.103150

Ivette M. Sandoval , Michael F. Salvatore , Fredric P. Manfredsson

The prospect of successful use of gene therapy to treat neurological disorders, including Parkinson’s disease (PD), can be increased by understanding the molecular etiology underlying disease symptoms and neurodegeneration. The major hurdle of safety for gene therapy use in central nervous system disorders has been cleared; with now ∼20 years since the first gene therapy clinical trial for PD, and with a large number of patients having received various treatments, the field has generated a large body of data with an impeccable safety record. As our understanding of the targetable components of disease processes evolves, so too do the tools available to target these processes. Viral vectors based on adeno-associated virus have undergone significant advancements in the last decade, including capsid improvements, enhanced production methods, and recombinant genome design. Although the etiopathology(ies) underlying PD is (are) yet to be defined, a number of therapeutic modalities with broad preclinical support have been, and are being, tested in humans. This includes proteins providing symptomatic relief, neuromodulation, monogenic correction, and neurotrophic support. The leading therapeutic gene therapy candidate has been glial cell line–derived neurotrophic factor (GDNF) or the closely related protein neurturin. Although clinical studies are still ongoing, recent work shows that protein levels of GDNF receptors (GDNF family receptor alpha1 and receptor tyrosine kinase) decrease with disease. Therefore, it is possible that optimal use of gene therapy using GDNF, and other protective pathways, can only be realized with an incisive assessment of all components of a targeted signaling pathway. Nevertheless, current clinical candidates, paired with a strong upcoming preclinical data pipeline, are setting the stage for an exciting future for PD gene therapy.

通过了解潜在疾病症状和神经退行性变的分子病因学，成功使用基因疗法治疗包括帕金森病（PD）在内的神经系统疾病的前景可以增加。基因治疗用于中枢神经系统疾病的安全性的主要障碍已经被清除；PD基因治疗首次临床试验至今已过去了20年，大量患者接受了各种治疗，该领域产生了大量数据，安全性记录无可挑剔。随着我们对疾病过程可靶向成分的理解不断发展，针对这些过程的可用工具也在不断发展。基于腺相关病毒的病毒载体在过去十年中取得了重大进展，包括衣壳改进、生产方法改进和重组基因组设计。尽管PD的病因病理学尚未明确，但许多具有广泛临床前支持的治疗方式已经并正在进行人体试验。这包括提供症状缓解、神经调节、单基因校正和神经营养支持的蛋白质。主要的基因治疗候选药物是神经胶质细胞系来源的神经营养因子（GDNF）或与其密切相关的神经蛋白。尽管临床研究仍在进行中，但最近的研究表明，GDNF受体（GDNF家族受体α 1和受体酪氨酸激酶）的蛋白水平随着疾病而降低。因此，只有对目标信号通路的所有成分进行深入评估，才能实现使用GDNF和其他保护途径进行基因治疗的最佳使用。然而，目前的临床候选药物，加上即将到来的强大的临床前数据管道，正在为PD基因治疗的激动人心的未来奠定基础。

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引用次数: 0

Corrigendum to “New insights into axonal regulators of dopamine transmission in health and disease” [Curr Op Neurobiol 94 (2025) 103093] “对健康和疾病中多巴胺传递轴突调节因子的新见解”的更正[Curr Op Neurobiol 94(2025) 103093]。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-18 DOI: 10.1016/j.conb.2025.103147

Kathryn L. Todd , Kaitlyn M.L. Cramb , Katherine R. Brimblecombe , Stephanie J. Cragg

引用次数: 0

Editorial overview: Molecular neuroscience 编辑概述：分子神经科学。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-17 DOI: 10.1016/j.conb.2025.103145

Yulong Li, Peter Scheiffele

引用次数: 0

Context matters: Conflicting roles of interferon-γ signaling in CNS diseases 背景问题：干扰素-γ信号在中枢神经系统疾病中的相互冲突的作用。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-16 DOI: 10.1016/j.conb.2025.103149

Jonathan Nulman , Jason D. Ulrich , David M. Holtzman

Interferon-gamma (IFNγ) is a pleiotropic cytokine produced by CD8+ and CD4+ Th1 T cells, natural killer cells, natural killer-T cells, and type 1 innate lymphoid cells. Canonical IFNγ-induced genes include cytokines, chemokines, antigen processing and presentation machinery, and other transcription factors that initiate secondary, cell type-specific IFNγ responses. Originally described as an antiviral molecule, additional roles for IFNγ in development, anti-infection immunity, and neurodegeneration have been described. However, IFNγ′s downstream effects are highly context-dependent. Recent studies have uncovered extensive neuroimmune interactions within the CNS and implicated IFNγ in numerous CNS diseases, although these studies have produced conflicting results. This highlights a need for functional studies accounting for the spatial, temporal, and cellular complexities of CNS IFNγ signaling. Here, we summarize the current understanding of IFNγ signaling in CNS infections, multiple sclerosis/experimental autoimmune encephalomyelitis, and aging-associated neurodegenerative diseases and propose a framework for the design of future studies investigating the role of CNS IFNγ signaling.

干扰素γ (IFNγ)是一种由CD8+和CD4+ Th1 T细胞、自然杀伤细胞、自然杀伤T细胞和1型先天淋巴样细胞产生的多效细胞因子。典型的IFNγ诱导基因包括细胞因子、趋化因子、抗原加工和呈递机制，以及其他启动次级、细胞类型特异性IFNγ反应的转录因子。最初被描述为抗病毒分子，IFNγ在发育，抗感染免疫和神经退行性变中的其他作用已经被描述。然而，IFNγ的下游效应是高度依赖于环境的。最近的研究发现了中枢神经系统内广泛的神经免疫相互作用，并暗示IFNγ与许多中枢神经系统疾病有关，尽管这些研究产生了相互矛盾的结果。这强调了对CNS IFNγ信号的空间、时间和细胞复杂性进行功能研究的必要性。在这里，我们总结了IFNγ信号在中枢神经系统感染、多发性硬化症/实验性自身免疫性脑脊髓炎和衰老相关神经退行性疾病中的当前理解，并提出了一个框架，用于设计未来研究中枢神经系统IFNγ信号的作用。

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引用次数: 0

Bridging the gap between physics and biology of hearing: Timing and amplification 弥合物理和听觉生物学之间的差距：时间和放大

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-13 DOI: 10.1016/j.conb.2025.103148

Christine Petit , Paul Avan

In mammals, the exquisite sensitivity and frequency selectivity of sound analysis rests on properly timed cycle-by-cycle feedback that compensates for friction and tunes the mechanical resonances of the auditory sensory organ. This feedback must operate at the highest audible frequencies, more than 100 kHz in some species, a feat given that it relies upon voltage-driven conformation changes of a protein called prestin, which forms an array along the lateral membrane of outer hair cell endowing them with electromotility. In the first place, the voltage that actuates prestin results from mechanotransduction of sound-induced vibrations by a mechanosensitive protein complex hosted in hair cell microvilli called stereocilia, whose nanometric deflections must ensure ion channel activation within microseconds. Many molecular assemblies and configurations allowing mechanosensitive detection to be pushed to such physical scales in terms of displacement and time, a unique requirement of hearing among mechanosensory systems, are still under active investigations.

在哺乳动物中，声音分析的灵敏度和频率选择性依赖于适当的周期反馈，这种反馈补偿了摩擦，调节了听觉器官的机械共振。这种反馈必须在最高可听频率下运行，在某些物种中超过100千赫，这是一项壮举，因为它依赖于电压驱动的一种叫做prestin的蛋白质的构象变化，prestin沿着外毛细胞的外侧膜形成阵列，赋予它们电运动性。首先，驱动prestin的电压来自于毛细胞微绒毛（称为立体纤毛）中的机械敏感蛋白复合物对声音引起的振动的机械转导，其纳米级的偏转必须确保离子通道在微秒内被激活。许多分子组合和结构允许机械敏感检测在位移和时间方面被推到这样的物理尺度，这是机械感觉系统中听觉的独特要求，目前仍在积极研究中。

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