As we age, neurons build up damage to DNA, and repairing that DNA could no doubt reverse cognitive impairment with age. This is the bet of this team from the Massachusetts Institute of Technology (MIT) which demonstrates here, in animals and in the journal Nature Communications, that reactivating a repair enzyme can actually reverse age-related cognitive decline.
The key enzyme or gene is HDAC1 which is found to be essential in repairing DNA damage to genes involved in memory and other essential cognitive functions. Levels of this enzyme are often reduced in both elderly and “Alzheimer” patients.
Restore HDAC1 to counter cognitive decline related to age and dementia
In this study, the team explores what happens when HDAC1-mediated repair is blocked. To do this, the researchers eliminated HDAC1 in neurons and astrocytes in mice. The researchers show in these mice deprived of HDAC1, a more rapid accumulation of DNA damage of a certain type. Mice also lose some of their ability to modulate synaptic plasticity or the strength of connections between neurons. Older mice lacking HCAC1 score poorly on memory and spatial navigation tests. But scientists also show
that it is possible to reverse this damage with a drug that reactivates HDAC1 and thereby restore cognitive function.
HDAC1, an anti-aging molecule: The study suggests that restoring HDAC1 could therefore bring great cognitive benefits in people suffering from an age-related cognitive decline, pathological or not. HDAC1 really seems to play the role of an “anti-aging” molecule, explains the main author, Dr. Li-Huei Tsai, director of the Picower Institute for Learning and Memory of MIT: ““ While most neurodegenerative diseases occur during aging , activating HDAC1 could be beneficial in many conditions. ”
DNA aging and repair, what process? There are several members of the HDAC enzyme family, and their primary function is to modify the histones or proteins around which DNA is wrapped. These epigenetic modifications control the expression of genes. Here, the researchers find that the loss of HDAC1 leads to a specific type of oxidative DNA damage. However, similar damage to the DNA of brain cells has been observed in patients with Alzheimer’s. Finally, we know that the brain’s ability to eliminate these lesions decreases with age.
An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage, but HDAC1 is required to activate OGG1. When HDAC1 is missing, OGG1 does not activate and DNA damage is not repaired. Many of the genes that researchers have identified as more susceptible to this type of damage code for ion channels, which are essential for the function of synapses.
Targeting and treating neurodegeneration: this is a new hope that seems achievable today. Researchers on the same team have already scanned libraries of small molecules for potential drug compounds that activate or inhibit enzymes in the HDAC family. One of these molecules, exifone, does a good job of reducing the levels of oxidative damage to DNA in brain cells, also in mice, and improves cognitive functions – including memory.
It turns out that the drug Exifone was approved in the 1980s in Europe to treat dementia, but withdrew from the market due to adverse effects on the liver. There are other drugs that activate HDAC1 and research will therefore continue.
HDAC1 indeed appears to be a promising target for reversing age-related phenotypes and treating neurodegenerative diseases.
Source: Nature Communications 18 May 2020 HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease