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HDAC1 Activators Improve DNA Repair in Neurons to Treat Cognitive Decline


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Posted 25 May 2020 - 10:11 AM


HDAC1 is involved in a form of DNA repair, but levels decline with age, as well as in Alzheimer's disease. This leads to a greater accumulation of unrepaired oxidative DNA damage in neurons. Researchers here note that increased activation of HDAC1 appears to improve cognitive function via a reduction in this oxidative DNA damage. An HDAC1 activator drug has been tested as a treatment for dementia, but caused serious side-effects. Better compounds or other approaches may be able to obtain similar benefits without the harms.

There are several members of the HDAC family of enzymes, and their primary function is to modify histones - proteins around which DNA is spooled. These modifications control gene expression by blocking genes in certain stretches of DNA from being copied into RNA. In 2013, researchers linked HDAC1 to DNA repair in neurons. In the current paper, the researchers explored what happens when HDAC1-mediated repair fails to occur. To do that, they engineered mice in which they could knock out HDAC1 specifically in neurons and another type of brain cells called astrocytes.

For the first several months of the mice's lives, there were no discernable differences in their DNA damage levels or behavior, compared to normal mice. However, as the mice aged, differences became more apparent. DNA damage began to accumulate in the HDAC1-deficient mice, and they also lost some of their ability to modulate synaptic plasticity - changes in the strength of the connections between neurons. The older mice lacking HCAC1 also showed impairments in tests of memory and spatial navigation.

The researchers found that HDAC1 loss led to a specific type of DNA damage called 8-oxo-guanine lesions, which are a signature of oxidative DNA damage. Studies of Alzheimer's patients have also shown high levels of this type of DNA damage, which is often caused by accumulation of harmful metabolic byproducts. The brain's ability to clear these byproducts often diminishes with age. An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage, and the researchers found that HDAC1 is needed to activate OGG1. When HDAC1 is missing, OGG1 fails to turn on and DNA damage goes unrepaired. Many of the genes that the researchers found to be most susceptible to this type of damage encode ion channels, which are critical for the function of synapses.

Several years ago, researchers screened libraries of small molecules in search of potential drug compounds that activate or inhibit members of the HDAC family. In the new paper, researchers used one of these drugs, called exifone, to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1. The researchers used exifone to treat two different mouse models of Alzheimer's, as well as healthy older mice. In all cases, they found that the drug reduced the levels of oxidative DNA damage in the brain and improved the mice's cognitive functions, including memory. Exifone was approved in the 1980s in Europe to treat dementia but was later taken off the market because it caused liver damage in some patients. Researchers are optimistic that other, safer HDAC1-activating drugs could be worth pursuing as potential treatments for both age-related cognitive decline and Alzheimer's disease.

Link: https://news.mit.edu...dna-damage-0518


View the full article at FightAging




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