Current Opinion in Neurobiology最新文献

英文中文

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。

引用次数: 0

Neural basis of sexually dimorphic decision-making 两性二态决策的神经基础。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-11 DOI: 10.1016/j.conb.2025.103146

Megan Day , Carolina Rezaval

Animals continually arbitrate between incompatible behaviors: whether to feed or flee, mate or fight, sleep or explore. The brain must select, suppress, and sequence actions according to sensory inputs, internal state, and likely success. Sexual dimorphism adds complexity: males and females face distinct reproductive pressures and often resolve conflicts in divergent ways. Yet the neural mechanisms underlying sex-specific prioritization remain poorly understood. Drosophila melanogaster offers a powerful model for dissecting action selection at cellular and circuit resolution. Here, we synthesize recent advances revealing how sexually dimorphic neurons act as integrator hubs, combining sensory cues with internal states to bias choice in both sexes. Neuromodulators confer flexibility, dynamically reweighting priorities as circumstances shift. Dopamine, in particular, filters distracting stimuli and tunes evidence accumulation, enabling priorities to update as goals approach. These studies outline emerging principles of action selection across contexts and sexes and suggest conserved strategies for balancing drives across species.

动物不断地在不相容的行为之间进行仲裁：是吃还是逃，是交配还是打架，是睡觉还是探索。大脑必须根据感官输入、内部状态和可能的成功来选择、抑制和排序动作。两性二态性增加了复杂性：男性和女性面临着不同的生殖压力，往往以不同的方式解决冲突。然而，基于性别的优先排序的神经机制仍然知之甚少。黑腹果蝇为在细胞和电路分辨率上解剖动作选择提供了一个强大的模型。在这里，我们综合了最近的研究进展，揭示了两性二态神经元如何作为整合中心，将感官线索与两性的内部状态结合起来，以进行偏见选择。神经调节剂赋予灵活性，随着环境的变化动态地调整优先级。尤其是多巴胺，它可以过滤分散注意力的刺激，调整证据积累，使优先级随着目标的临近而更新。这些研究概述了跨环境和性别的行为选择的新原则，并提出了跨物种平衡驱动的保守策略。

引用次数: 0

Forward and backward prediction in learning and perception 学习和感知中的前向和后向预测。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-10 DOI: 10.1016/j.conb.2025.103144

Floris P. de Lange , Clare Press

Predictive processing frameworks have emphasized the role of forward prediction as a critical ingredient for learning and perceptual inference. We anticipate sensory events that are likely in the future on the basis of past and current sensory events. By comparing these forward predictions against incoming input, we can obtain an accurate estimate of the environment (i.e. perceive) and improve the predictions themselves (i.e. learn). Interestingly however, research in the field of statistical learning has taught us that backward predictive relationships - reflecting the probability of past events given present events - are learnt equally well. This questions the privileged status of forward-looking mechanisms. Here we discuss commonalities and differences between implications for learning and perception. We conclude that while forward and backward predictive relationships both shape learning, we retrieve future, but not past, predicted states during perception.

预测处理框架强调了前向预测作为学习和感知推理的关键成分的作用。我们在过去和现在的感觉事件的基础上预测未来可能发生的感觉事件。通过将这些前向预测与输入进行比较，我们可以获得对环境的准确估计（即感知）并改进预测本身（即学习）。然而，有趣的是，统计学习领域的研究告诉我们，反向预测关系——反映过去事件给定当前事件的概率——同样可以很好地学习。这对前瞻性机制的特权地位提出了质疑。在这里，我们讨论学习和感知暗示之间的共性和差异。我们的结论是，虽然向前和向后的预测关系都影响了学习，但我们在感知过程中获取的是未来而不是过去的预测状态。

引用次数: 0

Hippocampal and cortical contributions to statistical learning 海马和皮质对统计学习的贡献。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-12-01 DOI: 10.1016/j.conb.2025.103136

Irene Zhou, Nicholas B. Turk-Browne

The human brain is adept at extracting regularities from our environment, allowing us to behave adaptively and make predictions. Research on the neural basis of this statistical learning has diverged in recent years based on the brain mechanism being investigated and the timing and modality of the regularities. One literature has focused on the entrainment of neural oscillations to rapid auditory sequences in cortical regions. The other literature has focused on changes in the similarity of neural representations for slower visual sequences in the hippocampus. By reuniting these literatures, we identify a potential role for the hippocampus in generalizing over temporal variability and suggest how hippocampal-cortical interactions could support statistical learning.

人类的大脑善于从我们的环境中提取规律，使我们能够自适应地行动并做出预测。近年来，基于所研究的脑机制以及规律的时间和形态，对这种统计学习的神经基础的研究出现了分歧。一篇文献聚焦于皮层区域快速听觉序列的神经振荡的携带。其他文献关注的是海马体中较慢视觉序列的神经表征相似性的变化。通过重新整合这些文献，我们确定了海马体在概括时间变异性方面的潜在作用，并提出了海马体-皮层相互作用如何支持统计学习。

引用次数: 0

Mechanisms of proteostasis in neuronal development and plasticity 蛋白质在神经元发育和可塑性中的作用机制

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-28 DOI: 10.1016/j.conb.2025.103143

Beatriz Maio , Francesca Aria , Susana R. Louros , Emily K. Osterweil

The careful regulation of the protein lifecycle is important for cellular function, particularly during times of change. In neurons, the specializations needed to maintain the steady-state proteome at multiple subcellular domains and respond rapidly to activity have brought about unique mechanisms in messenger RNA (mRNA) translation and protein degradation. Recent research continues to illuminate these critical mechanisms, giving us a deeper understanding of the nervous system and identifying new targets for the treatment of neurological disorders. In this review, we highlight the new research shedding light on the mechanisms of proteostasis in brain development and plasticity. These studies emphasize the extent to which protein synthesis and degradation participate in brain function and how disruptions of proteostasis lead to disorders of the nervous system.

仔细调节蛋白质的生命周期对细胞功能是重要的，特别是在变化时期。在神经元中，维持蛋白质组在多个亚细胞结构域的稳态和对活动的快速反应所需的特化带来了信使RNA （mRNA）翻译和蛋白质降解的独特机制。最近的研究继续阐明这些关键机制，使我们对神经系统有了更深入的了解，并确定了治疗神经系统疾病的新靶点。在本文中，我们重点介绍了蛋白质停滞在大脑发育和可塑性中的新研究。这些研究强调了蛋白质合成和降解参与脑功能的程度，以及蛋白质平衡的破坏如何导致神经系统紊乱。

引用次数: 0

The genetics of autosomal recessive early-onset Parkinson's disease 常染色体隐性早发性帕金森病的遗传学研究。

IF 5.2 2区医学 Q1 NEUROSCIENCES

Current Opinion in Neurobiology

Pub Date : 2025-11-17 DOI: 10.1016/j.conb.2025.103141

Guillaume Cogan, Suzanne Lesage, Alexis Brice

Early-onset Parkinson's disease (EOPD) is usually defined as Parkinson's disease (PD) occurring before the age of 40–50 years. Unlike late-onset PD, EOPD is often due to pathogenic mutations in autosomal recessive genes. Two phenotypes can be distinguished: typical EOPD, which progresses slowly (PRKN, PINK1 and DJ-1), and atypical PD, often associated with additional symptoms (ATP13A2, FBXO7, DNAJC6, VPS13C, SYNJ1, PLA2G6). In this review, we will highlight recent advances and remaining challenges. The frequency of causal genetic mutations and the genotype-phenotype landscape of PRKN-associated PD has been refined. Long-read sequencing has solved several undiagnosed cases with a single PRKN mutation. Five new genes have been reported to contribute to EOPD associated with various neurological signs (PTPA, DAGLB, PSMF1, EPG5, SGIP1). Small molecules targeting PRKN dysfunctions are expected to enter clinical trials in the coming years, paving the way for targeted therapies in EOPD.

早发性帕金森病（EOPD）通常被定义为40-50岁之前发生的帕金森病（PD）。与迟发性帕金森病不同，EOPD通常是由常染色体隐性基因的致病突变引起的。可以区分两种表型：典型的EOPD，其进展缓慢（PRKN、PINK1和DJ-1），以及非典型PD，通常伴有其他症状（ATP13A2、FBXO7、DNAJC6、VPS13C、SYNJ1、PLA2G6）。在这篇综述中，我们将强调最近的进展和仍然存在的挑战。因果基因突变的频率和prkn相关PD的基因型-表型景观已被完善。长读测序已经解决了几个未确诊的单一PRKN突变病例。据报道，有5个新基因与EOPD相关，并伴有各种神经症状（PTPA、DAGLB、PSMF1、EPG5、SGIP1）。靶向PRKN功能障碍的小分子有望在未来几年进入临床试验，为EOPD的靶向治疗铺平道路。

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Current Opinion in Neurobiology

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