How brain cells repair their DNA reveals “hot spots” of aging and disease

The brain is the organ responsible for our personality, consciousness and ability to process our surrounding environment. It, quite simply, makes us who we are. Unfortunately, as we age it is not solely our body that begins to fail us, but our mind responsible for our identity also deteriorates. However, the process behind this deterioration has been largely unknown to scientists and has puzzled them for years.

Neurons are the intricate structures which constitute the brain and are the longest lived cells in the human body. They are responsible for receiving sensory input from the external world and communicate this information to the rest of the body. The longevity of neurons, and their capability to age in parallel with their organism, makes them particularly susceptible to decline due to age-related disruptions. This inevitable ageing process causes changes in brain size, vasculature, cells, gross morphology and genome stability. But it is the onset of cognitive decline that we are most likely to see and associate with growing old. Despite this, an incredible feature of the brain is its plasticity, whereby throughout our lifetime the brain is constantly forming new connections in an attempt to slow down the ageing process, preserve memory and prevent the decline of the self. However, to form new connections the cells of the brain must be functioning relatively well. Neurons inability to replicate their DNA, unlike other cells in the body, means that they must instead use repair methods to mend DNA damage and maintain genomic integrity. These repair mechanisms have been found to decline with age, yet little is known about how genomic instability arises to begin with and what specific mechanisms neurons have developed to protect the genome as it degenerates.

A recent study, by a team of scientists at the Salk Institute, has identified ‘hotspots’ within the brain that are linked to the processes of aging and disease. Where previous research has looked for sites of genomic damage, this innovative study instead searched for sites at which the genome is being massively repaired. Reid et. al used a newly developed Repair-seq method to locate DNA repair sites within the genome of stem cell-derived neurons. They administered these stem cell-derived neurons with nucleosides, the building blocks of DNA, and used imaging methods to identify areas that were using these nucleosides to make repairs to the damaged sites. The study, published in Science, identified DNA repair hotspots in regions which are crucial for the protection of genes essential for neuronal function and identity. They detected around 61,000 DNA repair hotspots, covering 1.6% of the genome, of which were distributed throughout the genome and located on all chromosomes. The sheer abundance and ubiquitous nature of these hotspots could be an indication of their importance in brain function. Furthermore, proteomic data discovered increased activity of DNA repair hotspots in aging, as well as the prevalence of genes in DNA repair hotspots that are enriched in Alzheimer’s disease.

As neurons age, DNA repair activity declines leading to increased frequency of mutations and unrepaired lesion accumulation. They proposed that this decline in DNA repair activity could be responsible for the dysregulation of these sites, as seen in ageing processes. For example, DNA lesion accumulation, without these repair efforts, drives age-associated changes and leads to a decline in neuronal function. Disruption to these repair systems has previously been linked to both developmental and age-associated neurodevelopmental diseases.

The study also compared the location and proximity of DNA repair hotspots with sites associated with neuronal aging in humans and found very close association. The authors suggested that genome instability could redistribute repair efforts away from these DNA repair hotspots to other unstable genomic sites. Although, researchers are still unsure as to whether the hotspots identified are neuron-specific or are present in other cell lineages. Additional investigation into whether DNA repair hotspots exist in other cell types could further aid our understanding of how age-related changes may drive differential aging and disease development in other tissue types. 

The most widely seen age-related cognitive change is memory decline. A study conducted by the Alzheimer’s Society has predicted that by 2040, with the current rate of prevalence, there will be over 1.5 million people in the UK living with dementia. Reid et al. ’s groundbreaking discovery of sites at which the process of ageing is most active could pave the way for the development of therapies for neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and other forms of dementia. Revolutionary discoveries, like that of the Salk scientists, are transforming the field of neuroscience and how we look at the treatment of conditions such as Alzheimer’s.

Written by Millie Chambers and edited by Shona Richardson

You can find Millie on Twitter @MillieChambers_