A New Theory Explains Somatic Mutations in Terminally Differentiated, Transcriptionally Active Neurons
Objective:
To explain the increased risk for somatic mutations in genes that are involved in mature neuronal function.
Background:
A new theory holds that all DNA is damaged at a constant rate, causing a constant rate of mutations (https://doi.org/10.3389/fspas.2022.1067491). The source of DNA damage is proposed to be minimum ionizing particle (MIP) radiation. Single-stranded DNA (ssDNA) is readily damaged by ionizing particle radiation; ssDNA is present during DNA duplication and transcription.
Design/Methods:
The literature was surveyed for conditions associated with DNA mutations in neurons. Reported relationships between mutation frequency and presence of DNA duplication or transcription were recorded, and for transcription a relationship between at-risk loci and mutation was investigated.
Results:
Since 2015 single-cell sequencing has revealed that mutations in single human neurons track developmental and transcriptional history. Formation of all CNS cells is completed in the first year of life; early, common somatic neuronal mutations thus mainly reflect duplication mutations after conception. After terminal differentiation neuronal genes with high transcription rates are prone to somatic mutation compatible with transcriptional mutations.
At AAN 2024 12 of 16 at-risk germline loci in the APP gene (Alzheimer’s disease, AD) and 4 of 5 loci in the SNCA gene (Parkinson’s disease, PD) were shown to consist of somatic hypermutation (SHM) hotspots. Assuming similar transcriptional activity of both genes, at least one mutation of any SHM hotspot on both alleles for sporadic disease expression, and disregarding the importance of other genes, then a constant rate of ssDNA damage and mutation during transcription of the large number at-risk AD SHM hotspots suggest that sporadic AD is much more common (<122/42=<9-fold) than PD.
Conclusions:
MIP radiation as the common source of ssDNA damage explains the existence of embryonal-neonatal duplication- and after terminal differentiation transcription-related CNS mutations. Gene-related neurodegenerative disease appears to depend on transcriptional activity and the number of at-risk loci.
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