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Genetic, epigenetic, and environmental factors contribute to the multifactorial disorder progressive supranuclear palsy (PSP). Here, we study epigenetic changes by genome-wide analysis of DNA from postmortem tissue of forebrains of patients and controls and detect significant ( P.
Epimutations appear early in the progression of cancer and often precede malignancy. Due to the importance of epigenetic changes in development and disease, a variety of techniques for the study of DNA methylation has been developed in recent years (2,3). The choice of the method mainly depends on the desired application. Epigenetics: 233: Medicine & Health Science Books @ Amazon.com. Epigenetics 1st Edition. By Jorg Tost (Editor). ISBN-13: 9233.
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Progressive supranuclear palsy (PSP) is a progressive and fatal neurodegenerative disease with a prevalence of 5−7/100,000. Disease onset is usually beyond 60 years of age and the average survival time is 6–7 years after onset. Symptoms include ocular motor dysfunction, postural instability, akinesia, cognitive dysfunction, and dysphagia, with the latter being the most frequent cause of death in PSP.PSP is neuropathologically defined by intracellular aggregation of the microtubule-associated protein Tau in neurofibrillary tangles and tufted astrocytes. The aggregates eventually cause neuronal cell death in the cerebral cortex, diencephalon, brainstem, and cerebellar nuclei.PSP is a “complex” disorder; genetic, environmental and epigenetic modifications contribute to disease. A variant of the gene MAPT is the major genetic risk factor in PSP. Variants of the genes STX6, EIF2AK3, and MOBP also increase the risk of PSP. Among environmental factors, advanced age is the best established risk factor.
Epigenetic modifications reported so far in PSP include aberrant DNA methylation at the MAPT locus, and miRNA dysregulation.In order to learn more about the possible relevance of epigenetic changes in PSP we set out to study epigenetic alterations at the DNA level in prefrontal lobe tissue of PSP patients. We describe significant DNA methylation differences between patients and controls at many CpG sites, amounting to 451 protein-coding genes.
While methylation differences only affect one or a few sites at most genes, highly significant ( ≥ 5%) hypermethylation is found at multiple sites associated with the gene DLX1. Functional analyses of both DLX1 and its antisense transcript DLX1AS are consistent with an important role of DLX1 in the pathogenesis of PSP. Differentially methylated sites in PSPThe genome-wide DNA methylation patterns of 94 PSP patients (72 ± 5.3 years; 57% male, 43% female) were compared to 71 controls (76 ± 7.9 years; 67% male, 33% female) without neurological or psychiatric diseases (Supplementary Data ). We studied prefrontal lobe tissue since it is consistently pathologically damaged in PSP, but less so than other brain regions. We estimated the amount of neuronal and non-neuronal cells in our samples, as described by Guintivano et al.
The percentage of neurons in PSP patients (median 36.1% of cells) did not significantly differ from the proportion of neuronal cells in controls (median 38.0% of cells; Wilcoxon test, P = 0.31) (Supplementary Fig.
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