Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
MS Center Noord Nederland, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Acta Neuropathol Commun. 2023 Jun 20;11(1):100. doi: 10.1186/s40478-023-01598-7.
Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria. Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons. We generated large scale 2D scanning transmission electron microscopy images ('nanotomy') of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution. We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury.
多发性硬化症（MS）的病理生理学包括炎症、脱髓鞘和神经退行性变，但疾病起始和进展的确切机制尚不清楚。病变的一个主要特征是缺乏髓鞘，这增加了轴突的能量需求，并需要适应线粒体的数量和大小。在病变之外，在正常外观的白质（NAWM）和正常外观的灰质（NAGM）中观察到微妙和弥漫性的改变，包括氧化应激增加、轴突密度降低以及髓鞘组成和形态的变化。在超微结构水平上，只有有限的数据可用于研究髓鞘轴突的改变。我们生成了大量非脱髓鞘脑组织的 2D 扫描透射电子显微镜图像（'纳米断层扫描'），这些组织来自对照和进展性 MS 供体，可以通过开放获取的在线存储库访问。我们观察到 NAWM 中髓鞘轴突的密度降低，但轴突横截面积没有减少。小的髓鞘轴突在 NAWM 中出现的频率较低，而大的髓鞘轴突出现的频率较高，而 g-ratio 相似。在 NAWM 中，轴突线粒体半径与 g-ratio 之间的相关性丢失，但在 NAGM 中没有丢失。在对照 GM 和 NAGM 中，髓鞘轴突具有相似的 g-ratio 和半径分布。我们假设 NAWM 中的轴突丢失可能通过剩余髓鞘轴突的肿胀以及随后调整髓鞘厚度来维持其 g-ratio 来补偿。轴突线粒体不能调整其大小以及髓鞘厚度的微调可能会使 NAWM 轴突及其髓鞘更容易受到损伤。
