Researchers from Canada and the USA have studied how Sanfilippo syndrome affects the white matter in the brain.
The white appearance of parts of the brain (called the white matter) is due to the fat-rich substance myelin. Typically, myelin wraps around and insulates the axons of neurons. This myelin sheath increases the speed of electrical signals down the axon, helping neurons to transmit messages in the brain and spinal cord. When myelin is damaged or destroyed, for example in diseases like multiple sclerosis, it affects the function of nerve cells in the body.
The researchers in this study aimed to investigate myelin and white matter health in Sanfilippo.
First, the team studied these in the brain of a mouse model of Sanfilippo type C that they had previously developed. They confirmed that the myelin sheath of neurons is impacted in these mice, with a disorganised structure and reduced thickness. The levels of important proteins associated with myelin were also reduced in samples from the spinal cord and in the corpus callosum (a large white matter structure that connects the two halves of the brain).
They examined the oligodendrocytes, which are cells that produce and maintain the myelin sheath around axons. There was a significantly reduced number of oligodendrocytes in the corpus callosum of the Sanfilippo type C mouse model compared to unaffected mice.
When they observed the oligodendrocytes under the microscope, they saw changes to important structures inside the cells involved in energy production and waste recycling. There was also an accumulation of heparan sulfate and other storage molecules often associated with Sanfilippo. The researchers suggest that the oligodendrocytes may be dysfunctional and cannot properly maintain the myelin sheath, leading to overall myelin loss.
By analysing post-mortem brain samples of two people who lived with Sanfilippo type C, the team confirmed that the effects they saw on myelin in the mice were also observed in patients: the axons of neurons in the patients’ corpus callosum showed signs of degeneration, the myelin sheath of these neurons appeared damaged, and there were significantly reduced levels of myelin-associated proteins in neurons from the corpus callosum and spinal cord.
A reduction in myelin-associated proteins was also seen in an additional three brain samples from patients with Sanfilippo types A, C and D, which were compared with age-matched, unaffected brain samples. Based on these results, the team suggest that myelin damage may be a feature of all subtypes of Sanfilippo.
This is the first time changes to brain myelin has been described in detail in Sanfilippo syndrome and provides new information about how Sanfilippo affects the central nervous system. This may encourage other researchers to measure indicators of myelin health when testing potential therapies in the laboratory. The team also suggests that measuring white matter in the brain in living patients via MRI scans may be a useful biomarker to track disease progression in patients.
The study was led by Professor Alexey Pshezhetsky from the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Centre, University of Montreal. It was supported by funding from the Canadian Institutes of Health Research and the Canadian Glycomics Network and reported in a publication in the journal Frontiers in Molecular Neuroscience.
Sanfilippo Children’s Foundation has provided Incubator grants to Prof Pshezhetsky to investigate chaperones for Sanfilippo type C and a secondary deficiency of neuraminidase in Sanfilippo (co-funded with Fundacja Sanfilippo (Poland), Sanfilippo Initiative (Germany), and the H.A.N.D.S. consortium (Associação Sanfilippo Portugal, Sanfilippo Barcelona, Sanfilippo Sud)). Recently, Sanfilippo Children’s Foundation and Cure Sanfilippo Foundation (USA) awarded a Translational grant to Prof Pshezhetsky to investigate combined stem cell transplantation and cathepsin B inhibitors as a treatment for Sanfilippo.
