小鼠皮质亢进性驱动垂死肌萎缩侧索硬化症的症状和病理。

IF 6.1 2区 医学 Q1 NEUROSCIENCES
Mouna Haidar , Aida Viden , Christin Daniel , Brittany Cuic , Taide Wang , Marius Rosier , Doris Tomas , Samuel A. Mills , Alistair Govier-Cole , Elvan Djouma , Nirma D. Perera , Sophia Luikinga , Valeria Rytova , Samantha K. Barton , David G. Gonsalvez , Lucy M. Palmer , Catriona McLean , Matthew C. Kiernan , Steve Vucic , Bradley J. Turner
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引用次数: 0

摘要

大脑上运动神经元和脊髓下运动神经元的退化定义了肌萎缩性侧索硬化症(ALS),但它们在ALS病理生理学中的联系尚不清楚。在这里,我们揭示了由上运动神经元高兴奋性介导的ALS神经变性的皮层起源。在健康成年小鼠中,兴奋性化学遗传学诱导的上运动神经元慢性高兴奋性诱导进行性运动缺陷、虚弱和ALS的核心病理特征,包括上运动神经元丢失、突触病理、皮质脊髓束变性和反应性胶质细胞增生。重要的是,上运动神经元的高兴奋性和丧失足以驱动下运动神经元及其远端轴突和神经肌肉连接的变性,并与脊髓星形胶质细胞和小胶质细胞的激活有关。皮层高兴奋性也触发了细胞质TAR DNA结合蛋白43 (TDP-43)在上运动神经元和下运动神经元的聚集,将高兴奋性置于ALS中TDP-43蛋白病变的上游。这些发现确立了ALS由上运动神经元介导的皮层起源,与贯穿中枢和周围神经系统的神经变性的顺行机制一致。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cortical hyperexcitability drives dying forward amyotrophic lateral sclerosis symptoms and pathology in mice
Degeneration of both upper motor neurons in the brain and lower motor neurons in the spinal cord defines amyotrophic lateral sclerosis (ALS), but how they are linked in ALS pathophysiology is unclear. Here, we uncover a cortical origin of neurodegeneration in ALS mediated by upper motor neuron hyperexcitability. Chronic hyperexcitability of upper motor neurons induced by excitatory chemogenetics in healthy adult mice induced progressive motor deficits, weakness and core pathological hallmarks of ALS, including upper motor neurons loss, synaptic pathology, corticospinal tract degeneration and reactive gliosis. Importantly, upper motor neuron hyperexcitability and loss were sufficient to drive degeneration of lower motor neurons and their distal axons and neuromuscular junctions, associated with astrocyte and microglial activation in spinal cord. Cortical hyperexcitability also triggered cytoplasmic TAR DNA binding protein 43 (TDP-43) aggregation in upper motor neurons and lower motor neurons, placing hyperexcitability upstream of TDP-43 proteinopathy in ALS. These findings establish a cortical origin of ALS mediated by upper motor neurons, consistent with an anterograde mechanism of neurodegeneration throughout the central and peripheral nervous systems.
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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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