Department of Clinical Neurosciences, Karolinska Institutet, Center for Molecular Medicine, Karolinska Hospital at Solna, Stockholm, Sweden.
Laboratory of Molecular Neurobiology, Department Medical Biochemistry and Biophysics, Biomedicum, Karolinska Institutet, Stockholm, Sweden.
J Neurosci Res. 2021 Mar;99(3):793-805. doi: 10.1002/jnr.24767. Epub 2020 Dec 25.
Demyelinating pathology is common in many neurological diseases such as multiple sclerosis, stroke, and Alzheimer's disease and results in axonal energy deficiency, dysfunctional axonal propagation, and neurodegeneration. During myelin repair and also during myelin homeostasis, mutual regulative processes between axons and myelin sheaths are known to be essential. However, proficient tools are lacking to characterize axon-myelin interdependence during (re)myelination. Thus, we herein investigated adaptions in myelin sheath g-ratio as a proxy for myelin thickness and axon metabolic status during homeostasis and myelin repair, by using axonal mitochondrial size as a proxy for axonal metabolic status. We found that axons with thinner myelin sheaths had larger axonal mitochondria; this was true for across different central nervous system tracts as well as across species, including humans. The link between myelin sheath thickness and mitochondrial size was temporarily absent during demyelination but reestablished during advanced remyelination, as shown in two commonly used animal models of toxic demyelination. By further exploring this association in mice with either genetically induced mitochondrial or myelin dysfunction, we show that axonal mitochondrial size adjusts in response to the thickness of the myelin sheath but not vice versa. This pinpoints the relevance of mitochondrial adaptation upon myelin repair and might open a new therapeutic window for remyelinating therapies.
脱髓鞘病变在许多神经疾病中很常见，如多发性硬化症、中风和阿尔茨海默病，导致轴突能量缺乏、轴突功能障碍传播和神经退行性变。在髓鞘修复和髓鞘稳态过程中，轴突和髓鞘之间的相互调节过程被认为是必不可少的。然而，目前缺乏有效的工具来描述（再）髓鞘化过程中的轴突-髓鞘相互依赖关系。因此，我们在此研究了髓鞘鞘层 g 比值的适应性，作为髓鞘厚度的替代物，以及在稳态和髓鞘修复期间轴突代谢状态，使用轴突线粒体大小作为轴突代谢状态的替代物。我们发现，髓鞘较薄的轴突具有更大的轴突线粒体；这在不同的中枢神经系统束以及不同的物种中都是如此，包括人类。在脱髓鞘过程中，髓鞘厚度和线粒体大小之间的联系暂时不存在，但在晚期再髓鞘化过程中重新建立，这在两种常用的毒性脱髓鞘动物模型中得到了证明。通过进一步探索在具有遗传诱导的线粒体或髓鞘功能障碍的小鼠中这种关联，我们表明轴突线粒体大小会根据髓鞘厚度进行调整，但反之则不然。这指出了线粒体在髓鞘修复过程中的适应性的重要性，并可能为髓鞘再生疗法开辟一个新的治疗窗口。
