  Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative
disease causing parkinsonian symptoms. Altered DNA methylation of the
microtubule-associated protein tau gene correlates with the expression changes
in Alzheimer's disease and Parkinson's disease brains. However, few studies
examine the sequences beyond the constitutive promoter.Objectives: Because
activating different microtubule associated protein tau gene control regions
via methylation might regulate the differential tau expression constituting the
specific signatures of individual tauopathies, we compared methylation of a
candidate promoter, intron 0.Methods: We assessed DNA methylation in the brains
of patients with different tauopathies (35 Alzheimer's disease, 10 corticobasal
degeneration, and 18 PSP) and 19 controls by intron 0 pyrosequencing. We also
evaluated methylation in an independent cohort of 11 PSP cases and 12 controls.
Frontal (affected by tau pathology) and occipital (unaffected) cortices were
analyzed.Results: In the initial samples, one CpG island site in intron 0
(CpG1) showed significant hypomethylation in PSP-affected frontal cortices when
compared with controls (p = 0.022). Such hypomethylation was observed in
replicate samples, but not in occipital cortices or other tauopathies. PSP and
control samples (combining the initial and replicate samples) remained
significantly different after adjustment for potential confounding factors
(age, H1/H1 diplotype; p = 0.0005). PSP-affected tissues exhibited
microtubule-associated protein tau RNA hyperexpression when compared with
controls (p = 0.004), although no correlation with CpG1 methylation was
observed.Conclusions: This exploratory study suggests that regions other than
the constitutive promoter may be involved in microtubule-associated protein tau
gene regulation in tauopathies and that intron 0 hypomethylation may be a
specific epigenetic signature of PSP. These preliminary findings require
confirmation.
