Brain and neural cell type proteomics reveal extracellular matrix proteins enriched in progressive multiple sclerosis

Progressive multiple sclerosis (PMS) is an autoimmune demyelinating disease of the central nervous system (CNS) in humans. PMS is defined by neuroinflammation and axonal damage with concurrent advancing neurological disability, although the underlying molecular mechanisms remain uncertain. To investigate the molecular basis of PMS, we used mass spectrometry to define proteomic profiles and specific protein changes in matched CNS tissues (cortex, white matter, and demyelinated lesions) from persons with PMS and age/sex-matched other disease controls (ODCs). These studies were examined further using proteomes of primary human neural cell types including neurons, astrocytes, microglia, oligodendrocyte progenitor cells (OPCs) and CNS tissues from PMS mouse models. Collagen-containing extracellular matrix (ECM) related proteins, including the annexin, S100, and AHNAK protein families, were significantly enriched in PMS white matter, especially within demyelinated lesions compared to matched ODC tissues. These enriched proteins showed increased abundance in astrocytes and microglia compared to neurons and OPCs. Annexin, S100, and AHNAK family proteins were also increased in the CNS of the cuprizone and experimental autoimmune encephalitis mouse models. These findings highlight the importance of ECM protein induction in CNS glial cells during PMS while also providing new diagnostic and therapeutic options for future investigation.

进展型多发性硬化（Progressive multiple sclerosis, PMS）是一类发生于人类中枢神经系统（Central Nervous System, CNS）的自身免疫性脱髓鞘疾病。PMS以神经炎症、轴突损伤伴随进行性神经功能残疾为特征，但其潜在分子机制目前仍不明确。为探究PMS的分子基础，本研究采用质谱法（mass spectrometry）对PMS患者与年龄、性别匹配的其他疾病对照（Other Disease Controls, ODCs）的匹配中枢神经系统组织（皮层、白质及脱髓鞘病灶）的蛋白质组图谱及特异性蛋白变化进行了分析。本研究进一步采用原代人神经细胞类型（包括神经元、星形胶质细胞、小胶质细胞、少突胶质前体细胞（Oligodendrocyte Progenitor Cells, OPCs））的蛋白质组以及PMS小鼠模型的中枢神经系统组织对前述研究进行了拓展验证。与匹配的ODC组织相比，含胶原的细胞外基质（Extracellular Matrix, ECM）相关蛋白（包括膜联蛋白、S100及AHNAK蛋白家族）在PMS患者白质中显著富集，尤其在脱髓鞘病灶内富集程度更高。与神经元及OPCs相比，这些富集蛋白在星形胶质细胞和小胶质细胞中的表达丰度显著升高。膜联蛋白、S100及AHNAK家族蛋白在铜腙（cuprizone）诱导的及实验性自身免疫性脑炎小鼠模型的中枢神经系统中也呈现表达升高。本研究结果凸显了PMS发生过程中中枢神经系统胶质细胞内细胞外基质蛋白诱导的重要性，同时也为未来的研究提供了全新的诊断与治疗候选方向。