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J Neurosci Res. 2015 Mar;93(3):424-32. doi: 10.1002/jnr.23497. Epub 2014 Oct 21.

Oxidative stress is independent of inflammation in the neurodegenerative Sanfilippo syndrome type B.

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Laboratoire d'Oncobiologie Moléculaire, Centre de Biologie Humaine, CHU Amiens Picardie, Amiens, France; EA 4666 Lymphocyte Normal et Pathologique et Cancer, Université de Picardie Jules Verne, Amiens, France.


Mucopolysaccharidosis (MPS) type IIIB is a genetic deficiency of α-N-acetylglucosaminidase, inducing accumulation of partially degraded heparan sulfate (HS) oligosaccharides in tissues. In the central nervous system, this accumulation is associated with microglial activation, neurodegeneration, and oxidative stress. We have already shown that HS activates microglial cells through toll-like receptor 4 (TLR4) and triggers neuroinflammation. The present study investigates whether oxidative stress is a direct consequence of inflammation or is an independent event directly caused by HS accumulation. The present study addresses causative links between oxidative stress and inflammation by analyzing the corresponding markers in the cortex of control mice, MPSIIIB mice (with neuroinflammation), and double mutant TLR4 knockout MPSIIIB mice (without neuroinflammation at early stages). Results showed that, although inflammation was not present in the cortex of 10-day-old double mutant MPSIIIB/TLR4(-/-) mice, the enzymatic activity of total superoxide dismutase (SOD) was already greater than in control animals. Moreover, at 3 and 8 months of age, the total enzymatic activities of glutathione peroxidase, SOD, and carbonyl protein levels in the cortex of MPSIIIB/TLR4(-/-) mice were similar to those measured in MPSIIIB mice and were higher than those in controls. The results indicate that the oxidative stress present at a very early stage in the brain of MPSIIIB mice is not the consequence of neuroinflammation. Insofar as it has an impact on the development of neurological disease, reducing oxidative stress might prevent or slow the progression of MPSIIIB.


TLR4; heparan sulfate; inflammation; lysosomal storage diseases; mucopolysaccharidosis; oxidative stress

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