Fruit flies shed light on ultra-rare Sanfilippo syndrome type C

02 Apr 2024

A team of South Australian researchers have developed the world’s first fruit fly models of Sanfilippo type C to study the disease with the support of Sanfilippo Children’s Foundation funding. The research has been published in the Journal of Inherited Metabolic Disease.

Sanfilippo type C is caused by a deficiency of the enzyme HGSNAT. This leads to the build-up of heparan sulfate and dysfunction in cells throughout the body, with the most prominent effects in the brain. The finer details of how the deficiency of HGSNAT leads to symptoms are not yet known and the development of treatments for type C is not as well advanced as for Sanfilippo subtypes A and B.

Both humans and fruit flies have HGNSAT, and fruit flies are also relatively quick and cheap to breed in the laboratory. This can make them a good model organism to investigate Sanfilippo type C and potential treatments.

The team developed and thoroughly examined three new fly models of Sanfilippo type C. One of the fly models had HGSNAT deficiency throughout all the cells of the fly’s bodies and brains. The other two were engineered to have HGSNAT deficiency only in neurons (cells in the nervous system that transmit electrical signals).

All of the models showed an increase in heparan sulfate levels and larger lysosomes, the part of the cell where heparan sulfate builds up.

Two of the three fly models had abnormalities in their synapses, the connections between neurons, and showed deficits in a climbing test that measures motor function (the ability to move). The third model, which had a neuron-only HGSNAT deficiency, may represent a slower progressing, or attenuated form of the disease, as these flies did not show the same changes in their synapses and were slower to develop the deficits in the climbing test.

All of the Sanfilippo type C fruit fly models demonstrated overall reduced activity levels compared to unaffected flies.

To further explore how HGSNAT deficiency affects different cell types in the brain, the team also engineered fruit fly models with HGSNAT deficient in cells called glia, or glial cells. Glia are essential to support brain function and can be involved in inflammation.

They found that some glial cell types were more critical for the fly’s climbing ability and activity levels - when HGSNAT was deficient in these cell types, the flies performed worse on these tests.

Using new fly models of Sanfilippo type C, this study highlights how different cell types in the brain may be associated with the development of particular Sanfilippo type C disease mechanisms and symptoms. This opens the door to using the flies to potentially test therapies for type C.

The study team included Laura Hewson, recipient of a Sanfilippo Children’s Foundation PhD top-up scholarship, and her supervisor Dr Louise O’Keefe from The University of Adelaide.