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神经轴突退变作为运动神经元疾病(MNDs)的共同机制:RNA失调的分子见解及新兴治疗靶点

Neuroaxonal Degeneration as a Converging Mechanism in Motor Neuron Diseases (MNDs): Molecular Insights into RNA Dysregulation and Emerging Therapeutic Targets.

作者信息

Sharbafshaaer Minoo, Pepe Roberta, Notariale Rosaria, Canale Fabrizio, Tessitore Alessandro, Tedeschi Gioacchino, Trojsi Francesca

机构信息

First Division of Neurology, Department of Advanced Medical and Surgical Sciences, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

Department of Advanced Medical and Surgical Sciences, MRI Research Center, University of Campania "Luigi Vanvitelli", 81038 Naples, Italy.

出版信息

Int J Mol Sci. 2025 Aug 7;26(15):7644. doi: 10.3390/ijms26157644.


DOI:10.3390/ijms26157644
PMID:40806770
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12347207/
Abstract

Motor Neuron Diseases (MNDs) such as Amyotrophic Lateral Sclerosis (ALS), Primary Lateral Sclerosis (PLS), Hereditary Spastic Paraplegia (HSP), Spinal Muscular Atrophy with Respiratory Distress Type 1 (SMARD1), Multisystem Proteinopathy (MSP), Spinal and Bulbar Muscular Atrophy (SBMA), and ALS associated to Frontotemporal Dementia (ALS-FTD), have traditionally been studied as distinct entities, each one with unique genetic and clinical characteristics. However, emerging research reveals that these seemingly disparate conditions converge on shared molecular mechanisms that drive progressive neuroaxonal degeneration. This narrative review addresses a critical gap in the field by synthesizing the most recent findings into a comprehensive, cross-disease mechanisms framework. By integrating insights into RNA dysregulation, protein misfolding, mitochondrial dysfunction, DNA damage, kinase signaling, axonal transport failure, and immune activation, we highlight how these converging pathways create a common pathogenic landscape across MNDs. Importantly, this perspective not only reframes MNDs as interconnected neurodegenerative models but also identifies shared therapeutic targets and emerging strategies, including antisense oligonucleotides, autophagy modulators, kinase inhibitors, and immunotherapies that transcend individual disease boundaries. The diagnostic and prognostic potential of Neurofilament Light Chain (NfL) biomarkers is also emphasized. By shifting focus from gene-specific to mechanism-based approaches, this paper offers a much-needed roadmap for advancing both research and clinical management in MNDs, paving the way for cross-disease therapeutic innovations.

摘要

运动神经元疾病(MNDs),如肌萎缩侧索硬化症(ALS)、原发性侧索硬化症(PLS)、遗传性痉挛性截瘫(HSP)、1型呼吸窘迫型脊髓性肌萎缩症(SMARD1)、多系统蛋白病(MSP)、脊髓延髓肌肉萎缩症(SBMA)以及与额颞叶痴呆相关的肌萎缩侧索硬化症(ALS-FTD),传统上一直被作为不同的疾病实体进行研究,每种疾病都有独特的遗传和临床特征。然而,新出现的研究表明,这些看似不同的病症在驱动进行性神经轴突退化的共同分子机制上存在交集。这篇叙述性综述通过将最新研究结果整合到一个全面的跨疾病机制框架中,填补了该领域的一个关键空白。通过整合对RNA失调、蛋白质错误折叠、线粒体功能障碍、DNA损伤、激酶信号传导、轴突运输失败和免疫激活的见解,我们强调了这些趋同途径如何在MNDs中形成一个共同的致病格局。重要的是,这种观点不仅将MNDs重新构建为相互关联的神经退行性模型,还确定了共同的治疗靶点和新兴策略,包括反义寡核苷酸、自噬调节剂(自噬调控剂)、激酶抑制剂和超越个体疾病界限的免疫疗法。还强调了神经丝轻链(NfL)生物标志物的诊断和预后潜力。通过将重点从基因特异性方法转向基于机制的方法,本文为推进MNDs的研究和临床管理提供了一份急需的路线图,为跨疾病治疗创新铺平了道路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e0/12347207/4860bda17f74/ijms-26-07644-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e0/12347207/ab10cf06db05/ijms-26-07644-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e0/12347207/4860bda17f74/ijms-26-07644-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e0/12347207/ab10cf06db05/ijms-26-07644-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a4e0/12347207/4860bda17f74/ijms-26-07644-g002.jpg

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本文引用的文献

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Targeting androgen receptor stability and degradation: approaches for developing a therapy for spinal and bulbar muscular atrophy.

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Pharmacol Res. 2025-8

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Mol Neurodegener. 2025-6-4

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