Deciphering ferroptosis in mucopolysaccharidosis III (MPSIIIB) mouse model

Sanfilippo syndrome (MPSIII) is caused by lysosomal dysfunction and accumulation of abnormal heparan sulphate in brain, leading to neurodegeneration. Ferroptosis is an iron-dependent cell death driven by the production of reactive oxygen species and lipids peroxidation. Ferroptosis is associated with various neurodegenerative diseases, where iron accumulates due to intrinsic brain dysregulation of iron metabolism.

We have previously shown that, iron dysregulation in the cerebral cortex is also a distinctive feature of MPSIII pathogenesis, but it remains to be determined whether MPSIII neurons are affected by ferroptosis. Thus, we investigate the ferroptotic signature in groups of WT and MPSIIIB mice at 5 months of age.

The results showed several specific markers of ferroptosis. The expression level of TFR1, an iron import was decreased, brain iron content was increased but ferritin levels was increased, confirming iron accumulation in MPSIIIB brain. The xc-/GPX4 negative ferroptosis regulatory system was reduced. Oxidative homeostasis was affected as shown by increased expression of SOD2, SIRT3, iNOS, and nNOS. Finally, the expression of lipid peroxidation genes (ACSLl4, LPCAT3) was increased, indicating accumulation of peroxide lipids.

Furthermore, we observed a significant increase in the abundance of the iron exporter, ferroportin in MPSIIIB brain, but immunohistological labeling indicated an increase in this protein only in neurons (identified by NeuN markers). However, FPN exhibited an abnormal intracellular-vacuolar location, suggesting inadequate targeting to the plasma membrane and implicating its role in neuron iron accumulation.

 

In summary, we conclude that in MPSIIIB, neuronal alterations are directly associated with iron accumulation and ferroptosis.