NEW YORK (GenomeWeb) – Somatic mutations that arise during the development of the brain may underlie some neurodegenerative disorders like Alzheimer's and Parkinson's disease, according to a new study.
In the study, published in Nature Communications today, researchers led by a team at the University of Cambridge in the UK found that samples from more than half of 54 brains from patients and controls harbored somatic mutations, some of which may account for their disease.
"Together, these findings establish developmental mutagenesis as a potential mechanism for neurodegenerative disorders and provide a novel mechanism for the regional onset and focal pathology in sporadic cases," the authors concluded.
Diseases like Alzheimer's and Parkinson's disease lead to toxic protein clumps and a loss of cells in specific brain regions. Most patients do not have a family history of the disease, though about 5 percent carry a germline variant in one of a few dozen genes that increases their risk.
The researchers speculated that somatic mutations in one of those genes that spread in a specific cell lineage during brain development could similarly contribute to neurodegenerative disease development. To study the prevalence of such mutations, they performed ultra-high depth sequencing across various brain regions and used a computational model of brain development to estimate the burden of somatic mutations in the population.
For their project, they sequenced 56 genes known to cause or predispose to common neurodegenerative disorders and 46 control genes expressed at low levels in the brain and are associated with cancer at high depth in 173 frozen brain samples from 20 Alzheimer's patients, 20 Lewy body disease patients, and 14 age-matched controls. In addition, they sequenced those genes in matched blood DNA samples for six of the subjects. From the data, they called somatic mutations that were only present in one brain region (single region mutations, SRMs) and others that were found in more than one sample of the same brain (multi region mutations, MRMs).
Overall, they found 18 somatic SRMs in the brain samples, which were equally likely to occur in any brain region and which involved both neurodegenerative disease genes and cancer genes. Based on their modeling, they estimated that each individual had between 100,000 and 1 million pathologically mutated cells and that about 11 percent of individuals in the simulation had one or more brain regions with a large number of mutated cells.
Further, given certain assumptions, they estimated that each individual is likely to have one focus of 10,000 to 100,000 cells with a pathologic mutation once their brain has fully developed. "Our model serves as an initial means to explore the prevalence of these mutated foci, suggesting that such foci are possessed by almost all individuals," they wrote. "These regions may have the potential to generate mutant proteins that form novel fibrillar structures, which could spread and cause different neurodegenerative diseases, or modify the clinical phenotype, depending on the original mutated gene."
The researchers also discovered 17 mutations that were present in more than one brain region, only one of which occurred in a neurodegenerative disease gene. Based on this, they estimated that such mutations are present diffusely across the brain in about 10 percent of humans. Sixteen of the MRMs were in cancer genes, most of them associated with myeloproliferative blood disorders, and the researchers speculated that they were derived from circulating blood cells rather than the nervous system.
"Our findings indicate that the human brain is highly likely to contain many zones of cells harboring somatic mutations, including mutations affecting neurodegenerative disease genes," they concluded. Although such mutations occur rarely during early brain development, they said, they may involve a large proportion of neurons in the brain.
"Our study was not sufficiently large to show this directly, but this provides a potential explanation for common sporadic neurodegenerative diseases which currently affect [about] 10 percent of people in the developed world," they noted. "It is conceivable that detecting these mutations during life will increase diagnostic precision, leading to new therapies, particularly if they involved targets amenable to pharmacological intervention within vulnerable neural circuits."