Researchers from the Massachusetts Institute of Technology (MIT) recently made an immense discovery that the HDAC1 enzyme plays a vital role in the repair of age-related DNA damage to genes associated with various cognitive functions and memory. Neurologists have shown that people living with Alzheimer’s disease can highly benefit from this suggested medication.
A Woman With Alzheimer’s
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The neurologists who used mice for their research proved that when the HDAC1 enzyme is lost, some DNA damage accumulates as the mice age. The most exciting part of this study is that these researchers discovered that this specific damage could be reversed to enhance cognitive function. Evidence shows that this can be accomplished by using a drug that will act as an activator for HDAC1.
The HDAC enzyme family has several members whose main work is to transform the proteins around which DNA is bound (histones). These modifications precisely control gene expression by blocking the copying of genes in individual segments of DNA into RNA.
The HDAC1 enzyme research
Observation showed that during the first few months, no discernible difference in the levels of DNA damage as compared to the normal mice. However, the difference became more evident as the mice aged. DNA damage started to build up in HDAC1-deficient mice, and they also lost some of their synaptic plasticity modulation ability. There were also alterations in space navigation assessment and memory in older mice lacking HDAC1.
The study revealed that a deficiency of HDAC1 caused a condition called oxo-guanine DNA damage of 8, signifying damage to oxidative DNA.
8-oxo-guanine DNA damage can, however, be repaired by an enzyme called OGG1, and the study reveals that the HDAC1 enzyme can activate OGG1. In cases where there is HDAC1 deficiency, OCG1 fails to activate, leaving the damage unrepaired. The researchers discovered that several genes that are more likely to suffer this type of damage are important to the function of synapses.
Target neurodegeneration
Several years ago, the authors of this new study, Tsai and Stephen Haggarty, studied groups of tiny molecules seeking to establish potential drug compounds that could inhibit and activate members of the HDAC family. One of the drugs chosen was Exifone, a drug approved in the 80s in Europe to treat dementia. In the current release research paper, Tsai and Pao have used exifone to see if it has the potential to reverse the age-related DNA damage, exhibited by mice with HDAC1 deficiency.
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The researchers used exifone on two groups of mice: a group of healthy old mice and another with Alzheimer’s. The drug boosted the cognitive abilities and memory of both groups of mice. In all cases, they found that the drug lowered levels of oxidative DNA damage in the brain and improved the cognitive functions of mice, including memory.
Tsai says she is optimistic that other safe HDAC1-activating drugs may be worth pursuing as potential treatments for age-related cognitive decline and Alzheimer’s disease.
FAQ: HDAC1 and Its Role in Cognitive Function and Alzheimer’s Disease
1. What is HDAC1, and why is it important?
HDAC1 is an enzyme that helps repair age-related DNA damage, particularly in genes associated with cognitive function and memory.
2. How does HDAC1 deficiency affect the brain?
Without HDAC1, DNA damage accumulates over time, leading to cognitive decline, memory issues, and loss of synaptic plasticity, which are linked to neurodegenerative diseases like Alzheimer’s.
3. What did the MIT study discover about HDAC1?
The study found that HDAC1 deficiency leads to oxidative DNA damage, but activating HDAC1 with a drug can reverse this damage and improve cognitive function.
4. What is 8-oxo-guanine DNA damage, and how is it related to HDAC1?
8-oxo-guanine is a type of oxidative DNA damage that can be repaired by the enzyme OGG1. HDAC1 is necessary to activate OGG1, so without HDAC1, the damage remains unrepaired.
5. What drug was tested to restore HDAC1 function?
Researchers tested Exifone, a dementia drug used in Europe in the 1980s, and found that it reduced oxidative DNA damage and improved cognitive function in mice.
6. Did exifone help only Alzheimer’s mice, or did it benefit healthy older mice too?
Both Alzheimer’s mice and healthy aged mice showed improvements in memory and cognitive abilities after treatment with exifone.
7. Can HDAC1 activation be a potential treatment for Alzheimer’s?
Yes, researchers believe that safe HDAC1-activating drugs could help slow or reverse cognitive decline in Alzheimer’s patients.
8. What are the next steps for this research?
Scientists are exploring newer, safer HDAC1-activating drugs that could be developed for human clinical trials.
References
Pao, PC., Patnaik, D., Watson, L.A. et al. HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease. Nat Commun 11, 2484 (2020). https://doi.org/10.1038/s41467-020-16361-y
