Larribau Mathilde, Rouahi Myriam, Santiago Christophe, Ausseil Jérôme, Karim Zoubida
University of Toulouse, INFINITY, INSERM UMR1291, CNRS UMR5051, Toulouse, France.
Laboratory of Biochemistry and Molecular Biology, Centre Hospitalo-Universitaire (CHU) Toulouse, Toulouse, France.
Front Mol Biosci. 2025 Mar 18;12:1476513. doi: 10.3389/fmolb.2025.1476513. eCollection 2025.
Sanfilippo syndrome (MPSIII) is a neurodegenerative disorder caused by enzyme deficiencies, leading to the toxic accumulation of heparan sulfate oligosaccharides in the brain. Emerging evidence suggests that ferroptosis, an iron-dependent form of cell death, contribute to neurodegeneration. To investigate ferroptosis in MPSIIIB, we examined its regulatory mechanisms and markers in MPSIIIB brains. Our results showed elevated iron levels, decreased mRNA expression of TFR1 and ZIP14 (involved in iron uptake) at 9 months of age, and increased protein levels of FTH (which stores intracellular iron) in MPSIIIB brains, indicating a potential link to ferroptosis. We also observed diminished levels of ferroptosis-neutralizing proteins (xc-/GPX4), while the protective pathway (Keap1-Nrf2) was activated. Oxidative homeostasis disruption was revealed by increased expression of genes encoding SOD2, SIRT3, iNOS, and nNOS enzymes. Increased expression of lipid peroxidation genes (ascl4 and lpcat3) further supported ferroptosis involvement. Furthermore, we analyzed protein abundance and brain immunostaining of the iron exporter FPN. Despite its high expression levels, this protein appeared misfolded and was insufficiently targeted to cellular plasma membrane, which might contribute to cellular iron retention. The co-localization of FPN with NeuN, a marker of neurons, demonstrates that only neurons are affected by this targeting defect, suggesting neuronal ferroptosis specifically in MPSIIIB. Overall, our findings evidenced of the involvement of ferroptosis in MPSIIIB pathogenesis, highlighting dysregulation in iron homeostasis, antioxidant defenses, and lipid peroxidation as key features of the disease.
桑菲利波综合征（MPSIII）是一种由酶缺乏引起的神经退行性疾病，导致硫酸乙酰肝素寡糖在大脑中有毒性积累。新出现的证据表明，铁死亡（一种铁依赖性细胞死亡形式）与神经退行性变有关。为了研究MPSIIIB中的铁死亡，我们检测了其在MPSIIIB大脑中的调控机制和标志物。我们的结果显示，在9个月大时，MPSIIIB大脑中铁水平升高，参与铁摄取的TFR1和ZIP14的mRNA表达降低，而储存细胞内铁的FTH蛋白水平升高，这表明与铁死亡存在潜在联系。我们还观察到铁死亡中和蛋白（xc-/GPX4）水平降低，而保护途径（Keap1-Nrf2）被激活。编码SOD2、SIRT3、iNOS和nNOS酶的基因表达增加揭示了氧化稳态的破坏。脂质过氧化基因（ascl4和lpcat3）表达增加进一步支持了铁死亡的参与。此外，我们分析了铁输出蛋白FPN的蛋白质丰度和脑免疫染色。尽管该蛋白表达水平很高，但它似乎发生了错误折叠，并且没有充分靶向到细胞质膜，这可能导致细胞内铁潴留。FPN与神经元标志物NeuN的共定位表明，只有神经元受到这种靶向缺陷的影响，提示MPSIIIB中存在特异性的神经元铁死亡。总体而言，我们的研究结果证明了铁死亡参与MPSIIIB的发病机制，突出了铁稳态、抗氧化防御和脂质过氧化的失调是该疾病的关键特征。
