■多发性硬化症(MS)是中枢神经系统的脱髓鞘疾病,其特征是炎症和免疫反应增加,氧化损伤,线粒体功能障碍,铁代谢异常导致脱髓鞘和轴突损伤。在MS中,不完全的髓鞘再生导致慢性脱髓鞘的轴突和变性,同时伴有残疾。这表明MS的髓鞘再生能力失败,然而,确切的潜在机制尚不清楚.我们旨在鉴定在MS组织中慢性非活动性白质病变和斑块周围白质中表达改变的蛋白质,以揭示潜在的病理生理机制。
■激光捕获显微切割与蛋白质组学相结合,用于从三个慢性MS个体和三个没有明显神经系统并发症的对照中询问福尔马林固定石蜡包埋的脑组织的空间变化。组织病理学图指导捕获不活跃的病变,斑块周围白质,和来自慢性MS个体的皮质以及来自对照组织的相应白质和皮质。通过液相色谱串联质谱法进行的标记自由定量用于发现各个脑区域之间的差异表达的蛋白质。
■除了确认已知在MS中受影响的几种髓磷脂相关蛋白的丢失,慢性非活动性MS病变的蛋白质组学分析揭示了髓鞘组装的改变,新陈代谢,和细胞骨架组织。与对照白质相比,MS无活性病变中的最高改变蛋白由PPP1R14A组成,ERMN,SIRT2、CARNS1和MBLAC2。
■我们的发现强调了慢性非活动性MS白质病变和斑块周围白质的蛋白质组变化,这可能对正常的髓鞘形成至关重要,生物能学,粘着斑,和细胞功能。这项研究强调了空间方法的重要性和可行性,例如基于激光捕获显微切割的MS脑组织病理不同区域的蛋白质组学分析。鉴定MS脑组织蛋白质组的空间分辨变化应有助于理解病理生理机制和开发新疗法。
UNASSIGNED: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by increased inflammation and immune responses, oxidative injury, mitochondrial dysfunction, and iron dyshomeostasis leading to demyelination and axonal damage. In MS, incomplete remyelination results in chronically demyelinated axons and degeneration coinciding with disability. This suggests a failure in the ability to remyelinate in MS, however, the precise underlying mechanisms remain unclear. We aimed to identify proteins whose expression was altered in chronic inactive white matter lesions and periplaque white matter in MS tissue to reveal potential pathophysiological mechanisms.
UNASSIGNED: Laser capture microdissection coupled to proteomics was used to interrogate spatially altered changes in formalin-fixed paraffin-embedded brain tissue from three chronic MS individuals and three controls with no apparent neurological complications. Histopathological maps guided the capture of inactive lesions, periplaque white matter, and cortex from chronic MS individuals along with corresponding white matter and cortex from control tissue. Label free quantitation by liquid chromatography tandem mass spectrometry was used to discover differentially expressed proteins between the various brain regions.
UNASSIGNED: In addition to confirming loss of several myelin-associated proteins known to be affected in MS, proteomics analysis of chronic inactive MS lesions revealed alterations in myelin assembly, metabolism, and cytoskeletal organization. The top altered proteins in MS inactive lesions compared to control white matter consisted of PPP1R14A, ERMN, SIRT2, CARNS1, and MBLAC2.
UNASSIGNED: Our findings highlight proteome changes in chronic inactive MS white matter lesions and periplaque white matter, which may be crucial for proper myelinogenesis, bioenergetics, focal adhesions, and cellular function. This study highlights the importance and feasibility of spatial approaches such as laser capture microdissection-based proteomics analysis of pathologically distinct regions of MS brain tissue. Identification of spatially resolved changes in the proteome of MS brain tissue should aid in the understanding of pathophysiological mechanisms and the development of novel therapies.