Single Enzyme Gains the Upper Hand in Two Types of Dementia

Scientists at the Gladstone Institutes scored a rare two-for-one gain by discovering an enzyme that controls the levels of a protein implicated in both Alzheimer’s disease and frontotemporal dementia.

“For some time, we have known that low levels of the protein progranulin are associated with these two forms of dementia and that increasing levels improves deficit in animal models of the two diseases,” said Steven Finkbeiner, MD, PhD, a senior investigator at Gladstone. “But how could we use that as a possible therapy? That’s what is exciting about our latest results.”

In a new study published in the Journal of Biological Chemistry, Finkbeiner’s team looked closely at progranulin, which is secreted from cells and controls inflammation. Having only one copy of the gene for progranulin causes frontotemporal dementia, the most common form of dementia in people under age 65, while having mutations in the progranulin gene is a risk factor for developing Alzheimer’s disease. Both conditions result in lower levels of progranulin in the brain.

“We wanted to know what might regulate the levels of progranulin,” said Amanda Mason, a former PhD student in Finkbeiner’s lab and lead author on the study. “Many processes in biology are controlled by adding or removing a small chemical group called phosphate, so we started there.”

The team used a genetic method to look for enzymes that help to remove phosphate groups in mice. Surprisingly, among the enzymes they found, one—serine/threonine protein kinase 1, or Ripk1 for short—increased the levels of progranulin inside and outside of the cells. The real bonus was that Ripk1 worked in mouse models of both Alzheimer’s disease and frontotemporal dementia. Interestingly, the effect did not depend on the removal of the phosphate groups from progranulin, which implies that the effect comes about through a nonenzymatic mechanism.

“This is an exciting finding,” said Finkbeiner. “Alzheimer’s disease was discovered over 100 years ago, and we have essentially no drugs to treat it. To find a possible new way to treat one disease is wonderful. To find a way that might treat two diseases is amazing.”