CFR Researchers Identify Regulator of Plasma Progranulin Levels

CFR Investigator Dr. Rosa Rademakers and team recently reported levels of the protein sortilin influence levels of progranulin. Dr. Rademakers has studied progranulin since it was first linked to frontotemporal dementia; she is an author on both of the seminal 2006 publications that reported mutations in progranulin cause frontotemporal dementia.

Her group subsequently showed that plasma progranulin levels accurately reflect mutation status; patients carrying a mutation in progranulin have plasma progranulin levels that are less than half of healthy controls. She also noted that there is a wide range of progranulin levels in healthy controls. Intrigued by this variability, she and her team searched for other factors that might regulate plasma progranulin levels and discovered sortilin. High levels of sortilin result in low levels of progranulin in plasma. And since low levels of progranulin lead to frontotemporal dementia, targeting modifiers of progranulin levels may be important therapeutically.

Simultaneously, Dr. Steven Strittmatter at Yale University independently identified sortilin as a progranulin binding partner. Dr. Rademakers commented, “While Dr. Strittmatter’s work was specifically aimed at the identification of a neuronal binding site for progranulin, we took an unbiased genetic approach to identify regulators of progranulin in human plasma. It was very exciting to see that both our studies independently identified sortilin as an important player in progranulin biology.”

Dr. Rademakers plans to expand these studies “to identify additional genes and proteins involved in the regulation of progranulin in brain and cerebrospinal fluid.” In addition, “Given that sortilin is able to regulate the levels of progranulin in humans, our laboratory has now initiated genetic studies of the sortilin gene to look for mutations and genetic risk variants in patients with frontotemporal dementia,“ Dr. Rademakers said.