By Michelle Jaffee
New research illuminates how loss of the protein progranulin may influence immune system function in the brain and periphery in aged mice. The findings help lay the groundwork for future research into mechanisms involving progranulin loss in relation to neurodegenerative diseases that have an immunological component.
The study, published in Frontiers in Immunology, was led by neuroscientists at the University of Florida, Emory University and the University of California, Los Angeles. It is part of a line of research aimed at discovering new neuroprotective strategies to thwart diseases including Alzheimer’s disease, frontotemporal dementia and Parkinson’s disease.
Led by senior author Malú Gámez Tansey, Ph.D., the research team focused on progranulin, a secreted protein encoded by the GRN gene in humans. Mutations in the gene have been linked to inflammation and neurodegenerative diseases.
In the new study, UF researchers teamed up with Jessica Rexach, M.D., Ph.D., of UCLA to perform gene co-expression correlational analyses of published mouse and human microglia data from GRN-deficient mice and people with GRN loss-of-function mutations. Their aim was to test a hypothesis that the GRN gene has a critical role in regulating the activation status of immune cell populations in both the central and peripheral immune system. To gauge the association between progranulin loss and immune dysregulation, the team used 19- to 24-month-old male and female GRN-deficient mice and littermates with sufficient progranulin. The team performed flow cytometry of brain and blood immune cells from aged progranulin-deficient mice and control mice.
“Our findings suggest that progranulin is an essential regulator of immune homeostasis in the periphery as well as the brain and particularly in males,” said Oihane Uriarte Huarte, Ph.D., a postdoctoral associate in UF’s department of neuroscience and an author on the paper. “In addition, we have identified that the glycoprotein non-metastatic melanoma protein B is regulated in the context of progranulin deficiency, suggesting that both proteins could modulate immune responses in a sex-specific manner.”
The next step in this line of research is to study the role of central-peripheral immune crosstalk in GRN-linked frontotemporal dementia in collaboration with Rexach and Steve Finkbeiner, M.D., Ph.D., of the Gladstone Institute with support from the NIH’s National Institute of Neurological Disorders and Stroke. Future experiments will test the consequences of loss of glycoprotein non-metastatic melanoma protein B on immune responses, lysosomal dysfunction, tau aggregation and neurodegeneration association with GRN-linked frontotemporal dementia, Tansey said.
“We hope these studies will help to develop new neuroprotective strategies to delay or halt neurodegeneration,” she said.