Having less progranulin triggers massive neuronal death in the brains of people with frontotemporal dementia (FTD), and new research suggests that hyperactive glial cells are to blame. In the first published characterization of a microglia-specific progranulin knockout mouse, scientists report that these animals ramp up neuroinflammation and lose neurons in response to toxin-induced injury just as dramatically as mice lacking progranulin altogether. The research “points a finger at microglial progranulin as being the key modulator of the neuroinflammatory response,” said Robert Farese Jr. of the Gladstone Institutes, San Francisco, California. Published online October 8 in the Journal of Clinical Investigation, the findings invigorates efforts to develop therapies that suppress inflammation in FTD and other neurodegenerative disorders by boosting progranulin levels in the brain.

Expressed widely and implicated in wound healing and inflammation, progranulin roused intrigue among neuroscientists when null mutations in this gene cropped up as a major cause of hereditary frontotemporal lobar degeneration (FTLD) (see ARF related news story on Baker et al., 2006, and Cruts et al., 2006; Gass et al., 2006). In the central nervous system, progranulin is expressed in neurons and microglia (Petkau et al., 2010)—even more so in glial cells responding to nerve injury (Moisse et al., 2009). Progranulin is then secreted. In several knockout strains, a shortage of the growth factor makes aging mice prone to CNS gliosis (Yin et al., 2010; Wils et al., 2012; Petkau et al., 2012; Ahmed et al., 2010; Ghoshal et al., 2012), and heightens their susceptibility to collagen-induced arthritis (Tang et al., 2011).

In the current study, first author Lauren Martens and colleagues tested whether a lack of progranulin would rev up inflammation in response to CNS injury. They injected wild-type and progranulin-deficient mice with MPTP, a toxin known to cause inflammation and kill dopaminergic neurons. The progranulin knockout mice lost 66 percent of their substantia nigra dopamine neurons, compared to a 37 percent loss in wild-type mice. Moreover, the progranulin-deficient mice had almost three times as many activated microglia.

The researchers also injected MPTP into microglia-specific progranulin knockout mice, which they generated by crossing floxxed granulin transgenic mice with mice expressing CD11b-Cre. Measuring MPTP-induced dopaminergic cell loss and neuroinflammation, the scientists found that “getting rid of progranulin in the microglial compartment was sufficient to produce the same effect as the total body knockout,” Farese said.

The same held true in cell culture experiments. The team isolated cortical neurons, microglia, and astrocytes from floxxed granulin transgenic mice, and selectively depleted granulin in microglia by infecting the mixed cultures with lentivirus expressing Iba1-Cre. That wiped out almost half the neurons while doing nothing to microglia or astrocytes, suggesting again that removal of microglial progranulin is all it takes to kill wild-type neurons, this time in vitro.

Are these effects on neuronal survival the handiwork of secreted factors? To find out, the researchers isolated rat cortical neurons and cultured them in media from wild-type or progranulin-deficient microglia that had been stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFNγ). The conditioned media from LPS/ IFNγ-treated progranulin-deficient microglia killed more neurons than the media from stimulated wild-type microglia. The data “indicate that activated progranulin-deficient microglia likely secrete factors that promote the death of wild-type neurons,” the authors wrote.

Examining this further, the team found that progranulin-deficient microglia produced more pro-inflammatory cytokines (TNFα, IL-1b, and IL-6) than did normal microglia. Progranulin-deficient glia also secreted more IL-10, an anti-inflammatory cytokine, though the extra IL-10 apparently could not counteract the inflammatory state induced by TNFα, IL-1b, and IL-6.

The research “effectively shows that the deleterious effects associated with loss of progranulin are predominantly due to its actions in microglia,” Benjamin Wolozin of Boston University, Massachusetts, told Alzforum. “It puts the focus of FTLD on inhibiting inflammation.” By confirming and extending prior reports of increased microgliosis in progranulin knockout mice and reduced survival of cultured progranulin-deficient neurons (see Yin et al., 2010; Kleinberger et al., 2010), the JCI work has “brought together some of these earlier findings and connected a lot of dots. It’s a unifying paper,” said UCSF’s Aimee Kao, lead author on a C. elegans study suggesting that progranulin protects neurons by dampening phagocytosis (see ARF related news story on Kao et al., 2011).

Farese said the study “gives more evidence that pursuing small molecules that raise CNS progranulin levels might be useful—not only for FTD but also other neurodegenerative diseases.” Progranulin mutations have also been linked to Alzheimer’s disease (AD) (Brouwers et al., 2008), and microglial progranulin expression is up in AD and amyotrophic lateral sclerosis (ALS) (Pereson et al., 2009); Irwin et al., 2009). Several labs are working on compounds that increase progranulin levels; a few of these work by blocking its degradation (Cenik et al., 2011; ARF related news story on Capell et al., 2011; ARF conference story).

Coauthor Li Gan’s group at UCSF, as well as Erik Roberson’s lab at the University of Alabama, Birmingham, are currently investigating if microglial progranulin deficiency in the conditional knockouts recapitulates the range of behavioral and pathological changes seen in progranulin knockout mice. In addition, Farese and colleagues are testing whether progranulin deficiency modifies disease in animal models of Parkinson’s, AD or ALS.—Esther Landhuis

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References

News Citations

  1. Birds of a Feather…Mutations in Tau Gene Neighbor Progranulin Cause FTD
  2. Progranulin—Curbs Phagocyte Appetites, Protects Neurons?
  3. Back to Basics? Boosting pH Puts Cells in Progranulin-Pumping Mode
  4. Could Sortilin Be a Sweet Spot for FTD Therapy?

Paper Citations

  1. . Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006 Aug 24;442(7105):916-9. PubMed.
  2. . Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature. 2006 Aug 24;442(7105):920-4. PubMed.
  3. . Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration. Hum Mol Genet. 2006 Oct 15;15(20):2988-3001. PubMed.
  4. . Progranulin expression in the developing and adult murine brain. J Comp Neurol. 2010 Oct 1;518(19):3931-47. PubMed.
  5. . Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res. 2009 Jan 16;1249:202-11. PubMed.
  6. . Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010 Jan 18;207(1):117-28. PubMed.
  7. . Cellular ageing, increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice. J Pathol. 2012 Sep;228(1):67-76. PubMed.
  8. . Synaptic dysfunction in progranulin-deficient mice. Neurobiol Dis. 2012 Feb;45(2):711-22. PubMed.
  9. . Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging. Am J Pathol. 2010 Jul;177(1):311-24. PubMed.
  10. . Core features of frontotemporal dementia recapitulated in progranulin knockout mice. Neurobiol Dis. 2012 Jan;45(1):395-408. PubMed.
  11. . The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science. 2011 Apr 22;332(6028):478-84. PubMed.
  12. . Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem. 2010 Nov;115(3):735-47. PubMed.
  13. . A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells. Proc Natl Acad Sci U S A. 2011 Mar 15;108(11):4441-6. PubMed.
  14. . Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology. 2008 Aug 26;71(9):656-64. PubMed.
  15. . Progranulin expression correlates with dense-core amyloid plaque burden in Alzheimer disease mouse models. J Pathol. 2009 Oct;219(2):173-81. PubMed.
  16. . Progranulin (PGRN) expression in ALS: an immunohistochemical study. J Neurol Sci. 2009 Jan 15;276(1-2):9-13. PubMed.
  17. . Suberoylanilide hydroxamic acid (vorinostat) up-regulates progranulin transcription: rational therapeutic approach to frontotemporal dementia. J Biol Chem. 2011 May 6;286(18):16101-8. PubMed.
  18. . Rescue of progranulin deficiency associated with frontotemporal lobar degeneration by alkalizing reagents and inhibition of vacuolar ATPase. J Neurosci. 2011 Feb 2;31(5):1885-94. PubMed.

Further Reading

Papers

  1. . Divergent patterns of cytosolic TDP-43 and neuronal progranulin expression following axotomy: implications for TDP-43 in the physiological response to neuronal injury. Brain Res. 2009 Jan 16;1249:202-11. PubMed.
  2. . Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J Exp Med. 2010 Jan 18;207(1):117-28. PubMed.
  3. . Increased caspase activation and decreased TDP-43 solubility in progranulin knockout cortical cultures. J Neurochem. 2010 Nov;115(3):735-47. PubMed.
  4. . Progranulin expression in the developing and adult murine brain. J Comp Neurol. 2010 Oct 1;518(19):3931-47. PubMed.

Primary Papers

  1. . Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J Clin Invest. 2012 Nov 1;122(11):3955-9. PubMed.