DNA mutations may impact pathology of Alzheimer’s Disease

by Trinity Cardinal

Lauren Dempsey, MS in Biomedicine and Law, RN, FISM News 

 

Researchers at Boston Children’s Hospital, Brigham and Women’s Hospital, and the Broad Institute have conducted a study that suggests that individuals with Alzheimer’s Disease have a higher incidence of mutations in neurons than seen in individuals of the same age that do not have the disease. They believe that these mutations can significantly impair brain function.

The research, which was published in Nature on April 20, details how researchers were able to use single-cell genome sequencing data to evaluate the neurons of the prefrontal cortex and hippocampus from 319 Alzheimers’ patients. These areas of the brain are important for executive function, planning, memory, decision making, and other cognitive functions. They found that in these individuals there were somatic mutations, but also a difference in the pattern of mutations when compared with neurotypical and normally aging brains. 

Our DNA is made up of four nucleotides, C, G, A, and T,  which form the structure of DNA and contain genetic instructions. Each nucleotide is paired with its base, C with G and A with T, however when DNA becomes damaged it can result in a change to the DNA sequence, impacting biological function and possibly leading to disease. Most of the time cells in the body can identify and repair damage to DNA. 

Dr. Christopher Walsh, Chief of Genetics and Genomics at Boston Children’s Hospital and an Investigator of the Howard Hughes Medical Institutes, and co-senior investigator on the study explained that “Cells have repair pathways to undo DNA damage, but our work shows that in Alzheimer’s disease, neurons can’t keep up with the repairs, so the damage is permanent and cumulative,” and added that “This work provides a new way of thinking about neurodegenerative diseases such as Alzheimer’s, suggesting that they impair the ability of neurons to use their genome.”

The study revealed that people with Alzheimer’s had increased nucleotide oxidation in their neurons and it seemed that genes that are essential to brain function appeared to be more vulnerable to mutations. Researchers were able to support this theory by measuring 8-Oxoguanine,  which is a marker for oxidative stress and DNA damage, and found that neurons were more oxidized in those with Alzheimer’s. This sheds some light on the neurodegenerative process and the impact molecular and cellular events have on the development of Alzheimer’s Disease. Dr. Michael B. Miller from Boston Children’s Hospital and Brigham and Women’s Hospital said “Our findings suggest that the sheer number of oxidative lesions and somatic mutations we observed in AD neurons may contribute to its pathology.”

As they continue to expand on what was discovered in this study, researchers identified two study limitations. First, two primary groups were evaluated: those with advanced Alzheimer’s Disease and those with no documented neurological disease but, moving forward, the researchers want to evaluate patients in earlier stages of Alzheimer’s. Secondly, they hope to utilize more advanced methods of analyzing strands of DNA for future research. 

While research has shown that Alzheimer’s disease is caused by a loss of functional neurons, scientists cannot definitively say what causes this loss. Walsh has said that this is a step in the right direction, but the researchers “want to look at other neurodegenerative diseases like frontotemporal dementia, ALS, and chronic traumatic encephalopathy to see whether there’s a limit to the number of mutations in the brain that a neuron can tolerate,” adding “We’ve demonstrated that in Alzheimer’s disease, neurons cannot tolerate widespread oxidation of the genome, which results in permanent damage that can’t be fixed.”

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