Researchers from MIT’s Picower Institute for Learning and Memory are using a new approach in treating symptoms in people with Alzheimer’s disease (AD). An enzyme called HDAC2 is known to block memory-linked genes and is found in high levels in AD patients. Another and earlier approach for reducing HDAC2 activity has been to develop compounds that directly block HDAC2. These are called HDAC inhibitors. However, these compounds block not only HDAC2 but also a related enzyme called HDAC1. HDAC1 is crucial to white blood cells and other cells in the body and blocking it will lead to side effects.
Alzheimer’s disease is a degenerative disease characterized by memory loss and decline in cognitive abilities. Symptoms usually develop slowly and gradually worsen over time. While the greatest known risk factor is increasing age, the disease itself is not a normal part of growing old. After symptoms appear, people with AD generally have four to 20 more years, depending on age and condition. There is no cure for AD but symptoms can be slowed down and quality of life can be improved. In 2015, there were 29.8 million people with AD worldwide.
HDAC (or histone deacetylase) is a family of around 12 enzymes, the role of which is to regulate how genes are expressed. As the name suggests, they modify structures of histones through a process called “deacetylation”. Histones are proteins that act as spools around which a DNA winds; histones and DNA forms a network called chromatin.
Whenever histones undergo either “deacetylation” or “acetylation”, the structure of the chromatin is modified too in different ways. To simply describe the mechanism, acetylation will relax the chromatin and exposes the DNA. On the contrary, deacetylation tightens the chromatin, hides parts of the DNA and turns off a few genes that they cannot be expressed. HDAC promotes deacetylation and therefore will prevent certain genes from being expressed. Among HDAC, it is HDAC2 that affects memory-linked genes.
To combat memory loss associated with AD, HDAC inhibitors are used to counter HDAC2 activity. Again, due to the generic response of these inhibitors to several types of HDAC, researchers have looked for a better way of blocking HDAC2 only. So instead of directly blocking HDAC2, the current approach of MIT researchers is to block a gene within the chromatin which acts as HDAC2’s binding partner.
To identify this gene, researcher Li-Huei Tsai studied data from postmortem brain samples of people with and without Alzheimer’s disease. She found 2,000 genes that are associated with high HDAC2 levels. From 2,000 genes, they settled on one: the Sp3 gene. This gene was found to be “recruiting” HDAC2 into the chromatin. If Sp3 is blocked, HDAC2’s chances of moving towards the chromatin and blocking memory-linked genes are diminished.
To block Sp3, researchers have designed a protein fragment which has a similar structure to HDAC2’s binding part. However, the protein, which has 90 amino acids, is too large to be manufactured as a drug. Researchers are now looking for a smaller protein that is equally effective as Sp3 blocker. In case they cannot achieve this, there are still other genes aside from Sp3 that can be used for drug designs. This will also be helpful for other conditions associated with high HDAC2 levels like post-traumatic stress disorder.
Reference: MIT News