Researchers at the 8th International Conference on Frontotemporal Dementias, held 5-7 September in Manchester, U.K., got something new to think about with respect to how the cell controls expression of the disease-linked gene progranulin. Julia Strathmann of the German Center of Neurodegenerative Diseases (DZNE) in Munich explained how methylation of progranulin’s promoter turns down the gene. “We have identified new insights into how progranulin expression can be controlled, namely, by DNA methylation,” Strathmann wrote in an e-mail to Alzforum. Drugs that remove those methyl groups might boost progranulin and thus treat the disease, she suggested in an interview.

Strathmann’s talk received an award for the best oral presentation by a young researcher at the Manchester conference. Methylation was a hot topic at the meeting; speakers described how a different kind of methyl modification—to proteins—causes mislocalization of FUS, another dementia-linked protein (see ARF related news story on Dormann et al., 2012).

People carrying certain progranulin mutations, who suffer frontotemporal lobar degeneration (FTLD), have lower-than-normal concentrations of progranulin in their blood (Sleegers et al., 2009). However, “the physiological regulation of progranulin expression in the nervous system remains largely unexplored,” noted Louis De Muynck of VIB Leuven, Belgium, in an e-mail to Alzforum. De Muynck attended the meeting but was not involved in the study. Strathmann’s work begins to chart that new territory.

Among healthy people, and even those with sporadic FTLD, progranulin concentration in the blood differs measurably. One study found that those with the wild-type gene had anywhere from 125 to 375 nanograms of the protein per milliliter of plasma, regardless of FTLD status (Finch et al., 2009). Strathmann, who earned her graduate degree in an epigenetics lab and now works with Dieter Edbauer, followed a hunch that methylation might influence progranulin expression. Methyl groups, attached to cytosine- and guanine-rich sequences, often suppress genes.

Strathmann examined lymphoblasts obtained from several healthy controls, as well as from two patients with progranulin missense mutations. The amount of progranulin mRNA present and the concentration of the protein secreted into the culture media differed among the cells. By quantitative mass spectrometry, she determined that methylation of the progranulin promoter explained the pattern. There was a textbook inverse correlation, she said. The more methylated the promoter, the less progranulin the cell made. Using a drug called decitabine, which blocks DNA methyltransferases, she was able to boost progranulin mRNA and protein in the lymphoblasts.

What about in the brains of people with FTLD? Strathmann, in collaboration with Christine Van Broeckhoven of the University of Antwerp, Belgium, measured progranulin promoter methylation in brain tissue from five healthy controls and 10 people who had FTLD, including four people with progranulin mutations, two with mutations in another FTLD gene, VCP, and four with sporadic disease. The researchers observed a “small but significant” increase in progranulin promoter methylation in all FTLD cases, Strathmann said. There was also a trend toward lowered progranulin mRNA in the brain samples from FTLD cases, Strathmann wrote in an e-mail, but she was unable to examine progranulin protein levels in this tissue.

Researchers led by Daniela Galimberti at the University of Milan, Italy, recently found the same link between progranulin methylation and expression (Galimberti et al., 2012). Amid white blood cells from 38 people with sporadic FTLD, the progranulin promoter was methylated at 62 percent of possible sites, on average, compared to 46 percent among controls. “The methylation likely leads to a decreased expression of progranulin,” Galimberti wrote. She also observed a trend toward less progranulin in the FTLD cases, and a correlation between methylation and expression, but this was not statistically significant. In addition, the Milan researchers observed a wide range of methylation values and plenty of overlap between patients and controls.

“This hypermethylation is probably not the sole cause of why these people developed FTLD,” Strathmann wrote in an e-mail. In contrast, progranulin levels clearly distinguish those with mutations in the gene from sporadic FTLD and healthy controls (Finch et al., 2009). Thus, the loss of progranulin due to mutations is a much stronger effect than the downregulation by methylation, making mutation status a better marker for disease, Strathmann wrote.

Strathmann also tested brain samples for expression of methyltransferases by quantitative reverse transcriptase polymerase chain reaction. She found that the FTLD cases had more of the mRNAs for the DNA methyltransferases Dnmt1 and Dnmt3a, compared to controls. Since these enzymes modify many targets, Strathmann now plans to look for altered epigenetic patterns across the genome in FTLD.

“This study provides us with important new insights into how progranulin expression is regulated,” commented Peter Heutink of the VU University Medical Centre in Amsterdam, The Netherlands, in an e-mail to Alzforum. Heutink, who was not involved in the research, also noted it raises new questions. Is the methylation pattern set, or dynamic over time? Might other epigenetic factors, such as histone modification, affect progranulin expression? And finally, can scientists alter the methylation? Attacking the epigenetic pattern would be an addition to other progranulin therapy ideas, such as preventing progranulin endocytosis (see ARF related news story) or administering small molecules that amp up its production, as in the work of De Muynck and others (see ARF related news story).—Amber Dance.

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References

News Citations

  1. Arginine Methylation Distinguishes ALS-FUS From FTLD-FUS
  2. Could Sortilin Be a Sweet Spot for FTD Therapy?
  3. Case Studies Crystallize Trial Ideas at FTD Conference

Paper Citations

  1. . Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J. 2012 Sep 11; PubMed.
  2. . Serum biomarker for progranulin-associated frontotemporal lobar degeneration. Ann Neurol. 2009 May;65(5):603-9. PubMed.
  3. . Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain. 2009 Mar;132(Pt 3):583-91. PubMed.
  4. . Progranulin gene (GRN) promoter methylation is increased in patients with sporadic frontotemporal lobar degeneration. Neurol Sci. 2012 Jul 14; PubMed.

Further Reading

Papers

  1. . Progranulin: a proteolytically processed protein at the crossroads of inflammation and neurodegeneration. J Biol Chem. 2012 Sep 21;287(39):32298-306. PubMed.
  2. . Frequency of progranulin mutations in a German cohort of 79 frontotemporal dementia patients. J Neurol. 2009 Dec;256(12):2043-51. PubMed.
  3. . GRN variability contributes to sporadic frontotemporal lobar degeneration. J Alzheimers Dis. 2010;19(1):171-7. PubMed.
  4. . Epigenetic mechanisms in neurological disease. Nat Med. 2012 Aug;18(8):1194-204. PubMed.
  5. . Epigenetic mechanisms governing the process of neurodegeneration. Mol Aspects Med. 2012 Jul 7; PubMed.