A new MIT research suggests a way to develop better treatments for Alzheimer’s disease. They have illustrated that blocking a key enzyme named HDAC2 could reverse memory loss in mice. This enzyme turns off genes by condensing them hardly.
For many years, researchers have been trying to build drugs to block HDAC2, but all these drugs block other enzymes – mostly member of HDAC family, generating harmful side effects. The MIT scientists have now discovered a new way to accurately target HDAC2, by halting its interconnection with a binding partner named Sp3. This could be big news for the future of Alzheimer’s treatment.
Scientist used a big protein fragment to interfere with enzyme HDAC2, but their aim is to target smaller molecules, which would be easier to utilize in drugs.
Back in 2007, Li-Huei Tsai found that blocking HDAC enzyme could reverse memory damage in mice. The main function of HDAC is to modify histones. These modifications condense chromatin, which makes genes less likely to be expressed.
In human cells, there are around a dozen types of HDAC. Tsai later discovered that HDAC2 causes blockade of genes linked to memory. It’s quite higher in Alzheimer’s patients (human) and in various mouse models of the disease. ‘If we can reduce HDAC2 levels, then we can remove the blockade and restore expression of of genes essential for memory and learning’, Tsai added.
The problem is HDAC-blocking drugs also affect HDAC1, which are essential for proliferation (creation of red and white blood cells). To target HDAC2 more accurately, Tsai examined gene expression data of 28 brains (with no Alzheimer’s disease) with high HDAC2 levels and 35 brains with low HDAC2 levels. She found that over 2,000 genes (whose level matched HDAC2 levels) might work in tandem with HDAC2.
The Current Experiment
Based on prior knowledge, the scientists picked out 3 out of 2,000 genes for further testing. They found that a gene called Sp3 is essential for recruiting HDAC2 to chromatin to pass its blockade of genes that are linked to memory. They also analyzed gene expression data of Alzheimer’s patients and discovered a perfect correlation between Sp3 and levels of HDAC2.
Scientists studied these effects of blocking HDAC2 in mice, and they discovered that deactivating Sp3 restored their ability to generate long-term memories. Scientists used a type of small RNA strand to accomplish the genetic “knockdowns”. However, to use the same methodology in humans, they would likely require to design a drug in the shape of a tiny protein.
Eventually, scientists spotted the part of the HDAC2 protein, which binds to Sp3. When they developed neurons to generate more of that HDAC2 fragment, the fragment sopped a large quantity of available Sp3, releasing the blockade of genes that are linked to memory. Moreover, the fragment didn’t interface with proliferation, eliminating all the side effects of previously used HDAC inhibitors.
The protein fragment used in the current experiment has around 90 amino acids. It is too big to be used as a drug. Therefore, scientists are trying to find a smaller segment that would still disrupt the HDAC2 and Sp3 interaction.
Li-Huei Tsai hopes to examine some of the other genes as well that correlate with HDAC2. She also plans to find whether the same technique could be used to treat other disorder that involve increased HDAC2 levels, like post-traumatic stress disorder.