Glossary:
DNA: Genetic information/ instructions
Epigenetics: Modifying factors that can affect expression of genes.
Histone: Proteins which DNA wraps around
Histone acetylation: Addition of an acetyl group to a histone
Histone deacetylation: Removal of an acetyl group from a histone
If a person with Huntington’s disease has children they have a 50% chance of passing on the disease. As most people are aware, this occurs because Huntington’s disease is a genetic disorder. Our genes are made up of DNA. DNA can be thought of as an ‘instruction manual’ to make proteins to build us. However, in Huntington’s disease the DNA ‘instruction manual’ differs and the proteins built may allow for Huntington’s symptoms to present, such as involuntary movement and rigidity.
What people may not be as aware of is that epigenetics can also play a role in disease. Epigenetics refers to the factors which can alter the expression of genes. To put this simply, if DNA is the’ instruction manual’, epigenetics can help determine what can be read within the manual. An epigenetic process of interest in Huntington’s disease is histone acetylation. Histones are proteins that DNA wraps around to make sure it can stay compact. Histones can be acetylated, meaning they have a chemical group added to them known as an acetyl group. In theory, this acetyl group can mean that the DNA ‘instruction manual’ is easier to read and therefore, easier to make proteins from.
Huntington’s disease clinical drug trials have taken place utilising histone deacetylase inhibitors (HDACi). This class of drugs prevent the acetyl group added to histones from being removed, in theory continuing to make the DNA easier to read. It was hoped that HDACi would help alleviate Huntington’s disease symptoms. These drugs were designed as previous Huntington’s disease models had shown a decrease in histone acetylation and so HDACi were used to combat this change. Pre-clinical studies have revealed promising results for HDACi’s. But, unfortunately, these failed to translate in clinical trials as no clinical benefit for Huntington’s patients was found.
A study by a group of scientists at the University of Auckland investigated why these clinical trials failed. This study was extensive and employed a variety of different Huntington’s disease models; including a cell line model (expressing 97Q mutant huntingtin), a mouse model (YAC128) and a sheep model (OVT73). This study also utilised human brain tissue, which was kindly donated to the Neurological Foundation Human Brain Bank. The aim was to gain insight into histone acetylation in each model.
Interestingly the cell line, sheep model and human brain tissue all showed an increase in histone acetylation. This was a big deal, as it was in direct contrast to what previous studies had found and could be a key to understanding why the HDACi clinical trials failed. In addition, the mouse model did not show a significant change in histone acetylation. Subsequently, this suggested that different Huntington’s models may display different epigenetics changes.
This study presented some really important findings as it indicates that future studies should consider the fact that epigenetic modifications seen in human Huntington’s disease can differ to what is seen in Huntington’s disease models. This also indicates that the sheep model may more closely reflect human Huntington’s disease epigenetic changes and may be a good model to use in future studies. This finding was exciting as an improved awareness of the epigenetic differences between Huntington’s disease models may unlock exciting new potentials for drug targets.
Find the original research article here: Inconsistencies in histone acetylation patterns among different HD model systems and HD post-mortem brains
About the Author:
Jessica has recently obtained a Masters of Science after spending a year in the Centre for Brain Research (CBR) at the University of Auckland completing her thesis. She has a passion for research and is currently working as a research technician at the CBR on an exciting new project investigating the neuropathology of X-linked Dystonia Parkinsonism, a neurodegenerative disease endemic to the Philippines. She values the importance of sharing scientific knowledge and hopes to help do this in an accessible way.
