De Luca Fabrizio, Besio Roberta, Lugli Emma, Pelloni Enrico, Casali Claudio, Pérez Franco Wendy, Gaiaschi Ludovica, Gola Federica, Cavallo Margherita, Milanesi Gloria, Forlino Antonella, Bottone Maria Grazia
Department of Biology and Biotechnology, University of Pavia, 27100, Pavia, Italy.
Biochemistry Unit, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
Mol Neurobiol. 2025 Jul 22. doi: 10.1007/s12035-025-05205-9.
Osteogenesis imperfecta (OI), also known as brittle bone disease, is a rare congenital connective tissue disorder linked to collagen I defects, commonly known for its skeletal implications. However, collagen fibers play several key roles also in the central nervous system (CNS) starting from CNS development, regulating axonal growth, synaptogenesis, and terminal differentiation of Schwann cells. Collagen I plays an active role in defining brain architecture and in the developing peripheral. Furthermore, collagen is associated with astrogliosis and scar formation, processes finely regulated by molecules that are also involved in the regulation of the oxidative stress pathway. The aim of this work was to evaluate possible alterations in the cerebellum of the Brtl mouse, a well characterized model of dominant OI, focusing on cerebellar morphology using hematoxylin-eosin and Picrosirius Red staining, both in bright-field and polarized light microscopy. Additionally, ultrastructural alterations in the different cerebellar neuronal populations were evaluated using transmission electron microscopy (TEM), along with the involvement of the oxidative stress pathway by analyzing the expression levels of specific REDOX markers, such as COX4, SOD2, GPX4, and NRF2. Our results clearly demonstrate morphological and ultrastructural changes in the cerebellum of OI mice, along with increased oxidative stress detected in different regions and cell populations of this CNS area, suggesting possible CNS damage driven by the mutated form of collagen I. This work represents the first report of strong morphological and ultrastructural alterations in several cerebellar areas of Brtl mice, as well as a direct impact on the oxidative stress pathway.
成骨不全症（OI），也被称为脆骨病，是一种罕见的先天性结缔组织疾病，与I型胶原蛋白缺陷有关，通常因其对骨骼的影响而为人所知。然而，胶原蛋白纤维在中枢神经系统（CNS）中也发挥着几个关键作用，从CNS发育开始，调节轴突生长、突触形成和雪旺细胞的终末分化。I型胶原蛋白在定义脑结构和外周发育中发挥着积极作用。此外，胶原蛋白与星形胶质细胞增生和瘢痕形成有关，这些过程受到也参与氧化应激途径调节的分子的精细调控。这项工作的目的是评估Brtl小鼠小脑可能存在的改变，Brtl小鼠是一种特征明确的显性OI模型，使用苏木精-伊红染色和天狼星红染色，在明场和偏振光显微镜下观察小脑形态。此外，使用透射电子显微镜（TEM）评估不同小脑神经元群体的超微结构改变，并通过分析特定氧化还原标志物如COX4、SOD2、GPX4和NRF2的表达水平来评估氧化应激途径的参与情况。我们的结果清楚地表明，OI小鼠小脑存在形态和超微结构变化，同时在该CNS区域的不同区域和细胞群体中检测到氧化应激增加，这表明I型胶原蛋白的突变形式可能导致CNS损伤。这项工作首次报道了Brtl小鼠几个小脑区域存在强烈的形态和超微结构改变，以及对氧化应激途径的直接影响。
