SAN FRANCISCO, CA. 10/8/12 - Graduate student Lauren Herl Martens, in the laboratory of CFR Basic Science Research Program Director Dr. Bob Farese at the J. David Gladstone Institutes, is lead author on a study published today entitled, “Progranulin deficiency promotes neuroinflammation and neuron loss following
toxin-induced injury.” CFR Investigators Drs. Eric Huang, Li Gan and Steven Finkbeiner are co-authors on the study. Their work, published in the Journal of Clinical Investigation, describes a potential mechanism to explain how loss of progranulin causes neurodegeneration.

Mutations in the gene for progranulin, which reduce the total amount of progranulin protein in the body by more than 50%, are a frequent cause of frontotemporal dementia. Ms. Martens and colleagues generated an animal model of frontotemporal dementia by genetically deleting progranulin in mice and then exposed those progranulin-deficient mice to chemical injury. They showed that brains of mice lacking progranulin exhibit increased neuronal loss and inflammation in response to injury.

Interestingly, loss of progranulin didn’t make neurons intrinsically more prone to die following the chemical insult. Rather, Ms. Martens said, “Loss of progranulin made microglia, the immune cells of the brain, become more inflammatory and release molecules that likely caused neurons to die.” Microglia compose the primary line of defense in the brain, continually scavenging for damaged neurons, plaques and foreign agents and removing them. If microglia become hyper-activated, however, they can cause damage.

She and colleagues went on to selectively remove progranulin from microglia, while leaving normal progranulin function in all other cells in the body, and showed that these animals also reacted similarly to chemical injury. They observed that loss of progranulin solely in microglia results in increased neuron death, suggesting that progranulin is required to attenuate inflammation in response to injury in the CNS.

These results indicate that loss of progranulin may contribute to frontotemporal dementia by causing microglia to behave abnormally. By analogy, sufficient levels of progranulin may help decrease inflammation and neuron death in other neurodegenerative diseases or following other brain injuries. Thus, therapies to raise progranulin levels in the brain may have broad clinical utility.