Novel Pathway, Potential Drug Target for FTD Identified

Progranulin Function Discovery in FTD May Lead to Drug Development

Laura Newman

September 26, 2011

September 26, 2011 — Deficiency of progranulin caused by progranulin gene mutations precedes neuron death in frontotemporal dementia (FTD), according to animal, cell culture, and human research published in the September 22 issue of Neuron.

"We've known that granulin is important in this disease, but we have known nothing about its function relative to normal function in the brain," principal investigator Daniel H. Geschwind, MD, told Medscape Medical News.

"The whole idea here is that genetics is opening up to a whole new view of frontotemporal lobe dementia," said Dr. Geschwind, who is the Gordon and Virginia MacDonald distinguished chair in human genetics and professor of neurology at the David Geffen School of Medicine at the University of California, Los Angeles.

In uncovering what happens on a molecular level, Dr. Geschwind said it may be possible to "identify drugs that can modulate the pathways and offer neuroprotection."

A genetic component is likely in FTD because family history has been found in up to 50% of cases. FTD accounts for approximately 1 in 4 cases of early-onset dementia and is currently the second most common cause of presenile dementia.

The disease often begins insidiously, with alterations in personality and behavior; notably, disinhibition, inertia, and loss of will. Language disorders, especially progressive nonfluent aphasia, occur frequently. No cure for FTD exists.

New Drug Target?

The investigators used a 3-part analysis to examine how progranulin works in signaling pathways in cell culture, in a gene-knockout mouse model, and in postmortem brain tissue. Using a weighted gene network analysis, they were able to see nodes in a networked pathway of interconnected genes.

"It helps identify causality," said Dr. Geschwind. The researchers found that a decrease in granulin destroyed brain cells' survival and increased activity of Wnt, a key signaling pathway.

"Within this pathway, we identified a major amplification [overexpression] in a specific receptor that Wnt binds to on the cell surface. We found this early in the disease process in cell culture, in mice, and in human brain tissue."

One molecule in the Wnt pathway that was most clearly regulated when progranulin was decreased was the protein FZD2, which is part of the receptor complex for Wnt. This finding was especially strong in the mice.

When the cultured neurons were made to overexpress FZD2, they became less prone to cell death, suggesting that the increase in expression of the Wnt pathway gene when progranulin expression is deficient is part of a neuroprotective mechanism.

Dr. Geschwind was quick to note that researchers need to gain a far more comprehensive understanding of the other players in the pathway that may interact with FZD2. However, he added, "increasing the overexpression of protein at this receptor and other parts of the Wnt pathway may provide a new drug target to treat [FTD]."

More Research Needed

Such a novel drug would be called a Wnt agonist. "However," he cautioned, "we do wonder whether that will be enough as over the long term a simple agonist may not be enough...we just don't know."

"This needs to be confirmed in much more depth," said Andrew Bateman, PhD, professor of medicine at McGill University, Montreal, Quebec, Canada, and director of the endocrine research laboratory, Royal Victoria Hospital, also in Montreal.

"Increasing the expression of one gene in a pathway may not have the same effects as globally increasing the expression of many genes in the same pathway, but it is consistent with results in other diseases. Assuming it is true in vivo, it is rather clever."

This work was supported by the Consortium for Frontotemporal Dementia, the National Institute of Aging, a National Institute of Neurological Disorders and Stroke Neurobehavioral Genetics Training Grant, the John Douglas French Alzheimer’s Foundation, the National Institute of Mental Health, and the National Institutes of Health. The authors and Dr. Bateman have disclosed no relevant financial relationships.

Neuron. 2011;71:1030-1042. Abstract