Messmer Miranda L, Salapa Hannah E, Popescu Bogdan F, Levin Michael C
Office of the Saskatchewan Multiple Sclerosis Clinical Research Chair, University of Saskatchewan, Saskatoon, SK, Canada.
Cameco MS Neuroscience Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada.
Ann Neurol. 2025 Feb;97(2):313-328. doi: 10.1002/ana.27114. Epub 2024 Oct 18.
Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS.
Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration.
We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS-A1) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS-A1), MS-A1 showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron-specific RBP, in cortical projection neurons in MS-A1 cases.
hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN-negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2025;97:313-328.
尽管多发性硬化症（MS）的治疗取得了进展，但持续的神经退行性变仍在推动残疾和疾病进展。隐匿性/缓慢扩展病灶（SELs）以及RNA结合蛋白（RBP）异质性核糖核蛋白A1（hnRNP A1）功能障碍分别是MS皮质的病理特征，并与残疾和神经退行性变密切相关。我们推测，在进展性MS中，神经元hnRNP A1功能障碍会导致神经退行性变，且会因隐匿性/SELs而加剧。
使用免疫组织化学方法，在健康对照和MS患者的大脑中检测神经元hnRNP A1病理变化（hnRNP A1的核质错位）。根据hnRNP A1病理严重程度对MS病例进行分层，以研究RBP功能障碍、脱髓鞘和神经退行性变之间的联系。
我们发现，隐匿性/SELs仅存在于MS组织的一个亚组中，该亚组的特征是相邻皮质灰质中神经元hnRNP A1病理变化（MS-A1）升高。与健康对照和hnRNP A1病理变化较低的MS（MS-A1）相比，MS-A1显示出神经退行性变的标志物升高，包括神经元丢失和损伤、脑萎缩、轴突丢失和轴突变性。此外，我们在MS-A1病例的皮质投射神经元中发现了一个形态完整但缺乏神经元特异性RBP NeuN表达的神经元亚群。
hnRNP A1功能障碍会导致神经退行性变，在进展性MS中可能会因隐匿性/SELs而加剧。NeuN阴性神经元的发现表明，一些皮质神经元可能仅受到损伤而未丢失。通过对MS皮质中的RBP病理进行特征描述，本研究对于理解驱动神经退行性变、残疾和疾病进展的致病机制具有重要意义。《神经病学年鉴》2025年；97:313 - 328。
