| Summary: | Hereditary Cystatin C amyloid Angiopathy (HCCAA) is a rare Icelandic genetic disease caused by a mutation in the cystatin C gene CST3, L68Q-CST3. The mutation results in accumulation of the mutant protein product as amyloid in various tissues, predominantly in cerebral arteries of patients causing their death from intracerebral hemorrhages. In addition to amyloid accumulation in cerebral arteries there is also a significant deposition of extracellular matrix (ECM) proteins. This is of interest for the pathology of the disease as ECM proteins have been implicated in “trapping” amyloid forming proteins and thus facilitating local amyloid formation. Previous unpublished data from microarray study revealed that there were differences in the gene expression of dermal fibroblasts from carriers of the L68Q-CST3 mutation compared to that of controls. For example, the carrier cells had elevated expression of select ECM protein genes. A detailed study on the genealogies of HCCAA families has shown that in the beginning of the 19th century the life expectancy of HCCAA patients was around 65 years; however, at the beginning of the 20th century the average life expectancy of carriers had dropped drastically to about 30 years and this average has been consistent since then. One plausible explanation for this reduction is a gradual change in some environmental factors that began around 1825 and reached saturation around 1900. One of the large environmental changes in Iceland during the 19th century was in the diet of Icelanders, before the 19th century the Icelandic diet could be roughly classified as a ketogenic diet. A ketogenic diet is defined as a diet that induces the production of ketone bodies as alternative energy sources. One such ketone body is ß-hyroxybutyrate, which has recently been shown to be a histone deacetylases inhibitor (HDACi). This raised the question whether epigenetic gene control, specifically histon acetylation, could be a factor in HCCAA pathogenesis. In this study eight HDACi of various specificity ...
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