Boasinha Ana Sofia, Murtinheira Fernanda, Solá Susana, Gomes Cláudio M, Herrera Federico
BioISI - Instituto de Biosistemas e Ciências integrativas, Faculdade de Ciências da Universidade de Lisboa, 1749-016, Lisbon, Portugal.
Departamento de Química E Bioquímica, Faculdade de Ciências, Universidade de Lisboa, 1749-016, Lisboa, Portugal.
Mol Neurobiol. 2025 May 19. doi: 10.1007/s12035-025-05057-3.
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurological disorder caused by mutations in the SACS gene, resulting in the loss of sacsin function. Sacsin is a multidomain protein that plays key roles in chaperone regulation, protein quality control, and neurofilament dynamics. Sacsin deficiency leads to disruption of intermediate filament and mitochondrial networks. S100B, a multifunctional brain-enriched protein, exhibits protective neuroprotective functions that include chaperone activity and interactions with filament proteins and mitochondria. In this study, we used an established astroglial C6 cell model of ARSACS to investigate the potential compensatory effects of S100B on sacsin loss with respect to neurofilament integrity and mitochondrial morphological and functional hallmarks. Our results demonstrate that sacsin deletion induces S100B upregulation at both mRNA and protein levels, with the S100B protein colocalizing with perinuclear nestin aggregates and filamentous mitochondria networks. Genetic silencing and pharmacological inhibition of S100B exacerbate filament protein aggregation and mitochondrial defects, while supplementation with exogenous recombinant S100B improves ARSACS hallmarks, including decreased nestin aggregates. These findings provide evidence for functional compensation of sacsin loss by S100B in glial cells, and suggests a potential role for glial cells in ARSACS.
魁北克-萨格奈常染色体隐性痉挛性共济失调（ARSACS）是一种早发性神经疾病，由SACS基因突变引起，导致sacsin功能丧失。Sacsin是一种多结构域蛋白，在伴侣蛋白调节、蛋白质质量控制和神经丝动力学中起关键作用。Sacsin缺乏会导致中间丝和线粒体网络的破坏。S100B是一种多功能的富含大脑的蛋白，具有保护性神经保护功能，包括伴侣蛋白活性以及与丝状蛋白和线粒体的相互作用。在本研究中，我们使用已建立的ARSACS星形胶质细胞C6模型，研究S100B对sacsin缺失在神经丝完整性以及线粒体形态和功能特征方面的潜在补偿作用。我们的结果表明，sacsin缺失在mRNA和蛋白质水平上均诱导S100B上调，S100B蛋白与核周巢蛋白聚集体和丝状线粒体网络共定位。S100B的基因沉默和药物抑制会加剧丝状蛋白聚集和线粒体缺陷，而补充外源性重组S100B则可改善ARSACS特征，包括减少巢蛋白聚集体。这些发现为S100B在胶质细胞中对sacsin缺失的功能补偿提供了证据，并提示胶质细胞在ARSACS中可能发挥作用。
