Clemson researchers and fruit flies could help find treatment for “childhood Alzheimer’s”

Fruit flies - along with researchers at the Clemson University Center for Human Genetics - could be the key to identifying potential therapeutics for Sanfilippo syndrome, a rare and fatal genetic metabolic disorder that is often referred to as childhood Alzheimer's.

Children with Sanfilippo syndrome lack a single enzyme necessary to break down and recycle heparan sulfate, a large, complex molecule that is important for cell-cell interactions.

When too much partially degraded heparan sulfate accumulates inside cells in a compartment known as the lysosome, it causes progressive damage, especially in the brain.

Children with Sanfilippo syndrome are healthy babies at birth. Their first symptoms appear as mild developmental delays.

Over time as the heparan sulfate builds to higher levels, children with the syndrome experience severe hyperactivity, disordered sleep, loss of speech, cognitive decline, cardiac issues, seizures, loss of mobility and death.

Trudy Mackay and Robert Anholt of the Center for Human Genetics

Looking for a treatment or cure

There is no treatment or cure. Most people with the syndrome will die in their teens or early 20s.

The CHG has received a two-year renewal grant from the Cure Sanfilippo Foundation, founded by South Carolina parents Glenn and Cara O'Neill after their daughter Eliza was diagnosed with the disorder.

"We know the enzymes, we know the mutations and we know the consequences of the mutations. What we don't know is why the brain, specifically, is affected the most," said Trudy Mackay, the director of the CHG and the Self Family Endowed Chair of Human Genetics.

That's where the fruit fly comes in. Drosophila melanogaster - the common fruit fly -shares 75% of disease-causing genes with humans and is a well-established genetic model for studying the underlying genetic causes of rare human diseases.

"Drosophila also has heparin sulfate and all of the enzymes in the same pathway that degrades it," Mackay said.

Two enzymes

CHG researchers are looking at two enzymes that are in the pathway: N-Sulfoglucosamine sulfohydrolase (SGSH) and alpha-N-acetylglucosaminidase (NAGLU), said Robert Anholt, Provost Distinguished Professor of Genetics and Biochemistry and Director of Faculty Excellence for Clemson's College of Science. SGSH defects cause Sanfilippo A, the most common and most severe subtype, while NAGLU defects cause Sanfilippo B.

Researchers at the CHG have seen evidence of excitability and sleep fragmentation in Drosophila models for Sanfilippo A and B, Mackay said.

The researchers can measure fruit fly sleep using a Drosophila activity monitor. The flies are put in small tubes, and the tubes sit in a device that is bisected by a laser beam. Every time the fly crosses the beam, an activity count is generated. Devices can measure 32 flies at a time. Sleep in Drosophila is measured as five minutes without generating an activity count.

"We can measure how much they sleep, the total number of five-minute periods of inactivity and how fragmented the sleep is," Mackay said.

Changes in the brain

The researchers can also look at how gene expression in the brain changes in the flies.

"We see changes in expression in components of the synapse and neurodevelopmental genes," Mackay said.

Researchers can identify human counterparts of the genes that were differentially expressed in flies with the mutations.

With this grant, CHG scientists will screen several drugs that are approved by the Federal Drug Administration for pediatric use to determine if they restore sleep patterns to normal in the mutant flies. The drugs will be selected based on known gene-drug interactions.

They will collaborate with other scientists who can test the drugs in other systems, such as cultured human cells.

Anholt said researchers don't have to target the defective gene itself but can look for therapies that will act indirectly on the affected gene. He said there are multiple enzymes in the heparan sulfate degradation pathway and there is the potential that a modifier that acts on one component of the pathway could have beneficial effects across the entire pathway.

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