Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry
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Promoter DNA methylation regulates progranulin expression and is altered in FTLD

Acta Neuropathologica Communications 1 (1):16

Authors/Editors: Julia Banzhaf-Strathmann
Rainer Claus
Oliver Mücke
Kristin Rentzsch
Julie van der Zee
Sebastiaan Engelborghs
Peter P De Deyn
Marc Cruts
Christine van Broeckhoven
Christoph Plass
Dieter Edbauer
Publication Date: 2013
Type of Publication: Journal Article

ABSTRACT:
Background

Frontotemporal lobar degeneration (FTLD) is a heterogeneous group of neurodegenerative diseases associated with personality changes and progressive dementia. Loss-of-function mutations in the growth factor progranulin (GRN) cause autosomal dominant FTLD, but so far the pathomechanism of sporadic FTLD is unclear.

Results

We analyzed whether DNA methylation in the GRN core promoter restricts GRN expression and, thus, might promote FTLD in the absence of GRN mutations. GRN expression in human lymphoblast cell lines is negatively correlated with methylation at several CpG units within the GRN promoter. Chronic treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine (DAC) strongly induces GRN mRNA and protein levels. In a reporter assay, CpG methylation blocks transcriptional activity of the GRN core promoter. In brains of FTLD patients several CpG units in the GRN promoter are significantly hypermethylated compared to age-matched healthy controls, Alzheimer and Parkinson patients. These CpG motifs are critical for GRN promoter activity in reporter assays. Furthermore, DNA methyltransferase 3a (DNMT3a) is upregulated in FTLD patients and overexpression of DNMT3a reduces GRN promoter activity and expression.

Conclusion

These data suggest that altered DNA methylation is a novel pathomechanism for FTLD that is potentially amenable to targeted pharmacotherapy.

 

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