Biochemical and metabolic maladaption defines pathological niches in progressive multiple sclerosis
Biochemical and metabolic maladaption defines pathological niches in progressive multiple sclerosis
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生化和代谢适应不良定义了进行性多发性硬化症的病理生态位
DOI：
10.1101/2022.09.26.509462
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Grant-Peters M
中科院分区：
文献类型：
--
作者：
Grant-Peters M
进行性多发性硬化症（MS）是由发生在闭合的血脑屏障（BBB）后面的脱髓鞘、神经轴突损失和线粒体损伤驱动的。进行性MS患者通常对可减少早期疾病复发的免疫调节药物无反应。这表明迫切需要确定非规范的治疗途径，以限制神经变性并促进保护和修复。在这里，我们采用了高分辨率的多组学分析来验证MS病理学基础上的生化和代谢适应，因为这些适应尚未完全描述，但很关键，可能适合于BBB渗透性药物靶向。使用同步辐射（SR）和焦平面阵列（FPA）为基础的傅里叶变换红外显微光谱（μFTIR），我们空间映射的生化特征存在于人类进行性MS和控制死后的大脑和罕见的脊髓组织。通过采用单核RNA测序（snRNA-seq），10 x Genomics Visium空间转录组学和空间蛋白质组学来解析它们的细胞背景，我们发现这些生化特征为组织内不同的病理小生境提供了独特且高度疾病特异性的条形码。对支持这些小生境的代谢过程的表征揭示了灰色和白色物质中星形胶质细胞景观的相关重组，这对治疗进行性MS具有意义。
Progressive multiple sclerosis (MS) is driven by demyelination, neuroaxonal loss, and mitochondrial damage occurring behind a closed blood-brain barrier (BBB).,Patients with progressive MS typically fail to respond to available immunomodulatory drugs that reduce relapses in early disease. This indicates a dire need to identify non-canonical therapeutic avenues to limit neurodegeneration and promote protection and repair. Here, we have employed high-resolution multiomic profiling to characterise the biochemical and metabolic adaptations underpinning MS pathology, as these have been incompletely described but critically, may be amenable to BBB-permeable drug targeting. Using synchrotron radiation (SR)- and focal plane array (FPA)-based Fourier transform infrared microspectroscopy (μFTIR), we spatially mapped the biochemical features present in human progressive MS and control post-mortem brain and rare spinal cord tissue. By employing single-nuclear RNA sequencing (snRNA-seq), 10x Genomics Visium spatial transcriptomics and spatial proteomics to resolve their cellular context, we found that these biochemical features provide a uniquely and highly disease-specific barcode for distinct pathological niches within the tissue. Characterisation of the metabolic processes underpinning these niches revealed an associated re-organisation of the astrocytic landscape in the grey and white matter, with implications for the treatment of progressive MS.
原发性进行性多发性硬化症患者的富马酸二甲酯治疗
DOI：
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发表时间：
2021
期刊：
Neurology: Neuroimmunology & Neuroinflammation
影响因子：
--
作者：
Helene Højsgaard Chow;J. Talbot;H. Lundell;Camilla Gøbel Madsen;Lisbet Marstrand;T. Lange;M. Mahler;Sophie Buhelt;Rikke Holm Hansen;M. Blinkenberg;J. Romme Christensen;P. Soelberg Sørensen;Marina Rode von Essen;H. Siebner;F. Sellebjerg
通讯作者：
F. Sellebjerg
Photizo：用于 FTIR 光谱数据跨样本分析的开源库
DOI：
10.1101/2022.02.25.481930
发表时间：
2022
期刊：
--
影响因子：
--
作者：
Grant-Peters M
通讯作者：
Grant-Peters M
影响因子：
64.8
作者：
Schirmer, Lucas;Velmeshev, Dmitry;Rowitch, David H.
通讯作者：
Rowitch, David H.