The childhood dementia Sanfilippo syndrome is marked by the accumulation of the complex sugar heparan sulfate (HS). While this causes the greatest impact in the brain in Sanfilippo, other parts of the body are affected too. The complexity of the disease means that researchers are still making new discoveries about how high levels of HS affect the tissues of the body.
A recently-published study, led by a team in France, has looked at how elevated HS in disorders like Sanfilippo affects the lungs of patients. They found that HS impacts the delicate balance between two key proteins: cystatin C and cathepsin L.
Cathepsin L is a ‘protease’ capable of cleaving proteins, and it is involved in many cell processes like the recycling of protein building blocks. Cystatin C can inhibit the function of cathepsin L, and the interaction between these molecules must be tightly controlled - both too much and too little cathepsin activity are associated with various lung diseases.
The researchers in the study collected respiratory samples from eleven patients with different types of mucopolysaccharidosis (MPS) that all involve the accumulation of HS - four patients with Sanfilippo, two with Hurler syndrome, and five with Hunter syndrome. They found that cystatin C levels were seven times higher in the patient samples compared to individuals without MPS. Higher cystatin C levels and higher HS levels also correlated with more severe respiratory symptoms.
With these very high levels of cystatin C, the researchers expected to find that the activity of cathepsin L would be inhibited, but they were surprised to find that cathepsin L was still active in the MPS lung samples.
Further experiments revealed that the very high levels of HS were blocking cystatin C from doing its job to limit the activity of cathepsin L.
After a deeper dive into the interaction between HS and cystatin C via molecular modelling, the team identified that HS can change the three-dimensional shape of cystatin C by binding to one of three likely regions on the enzyme. The team hope their analysis will inform future work to prevent HS binding to cystatin C to restore the balance between cystatin C and cathepsin L and therefore help restore lung function.
Because of the correlation between high cystatin C and respiratory symptoms, the researchers also note that cystatin C levels in patient sputum samples could potentially be used as a non-invasive biomarker to measure respiratory distress in patients with Sanfilippo, Hurler, and Hunter syndromes.
This study highlights how HS accumulation can cause secondary effects throughout the body that contribute to symptom severity. Looking at how higher HS levels impact other molecules and processes in the cell can help to understand Sanfilippo better and potentially identify treatments.
An Australian team are also looking at lung function in Sanfilippo syndrome with a grant from the Sanfilippo Children’s Foundation. They are investigating how the condition affects the lubrication in the lungs and the immune cells that are there to fight infection.