Somatic Single Nucleotide Variation in Alzheimer's Patients

By | Qi Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal loss and protein misfolding and deposition
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Although a large number of studies have been conducted to explain the formation mechanism of protein deposition, there is no consensus on what exactly is the core cause of cellular dysfunction in AD
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Somatic mutations can occur in postmitotic neurons and can gradually accumulate in a process known as “genosenium (representing the association of genome-genome and senescence)” [1, 2]
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AD patients exhibit increased oxidative stress and somatic single nucleotide variants (sSNVs), but the extent to which these sSNVs are repaired and whether they have long-term effects on genome structure remains unknown
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On April 20, 2022, multiple teams including Christopher A.
Walsh from Boston Children's Hospital collaborated to publish an article entitled Somatic genomic changes in single Alzheimer's disease neurons in the journal Nature.
They sequenced single-cell whole genome ( scWGS) was applied to AD individuals to elucidate information such as the type, quantity, and genomic location of somatic mutations associated with AD
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First, the researchers performed scWGS on pyramidal neurons isolated from the brains of AD and control individuals to identify sSNVs
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In normal PFC neurons, the age-related increase in mutations is mainly driven by certain C>T and T>C changes, termed signature A [1], whose contribution increases with age in all samples
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The AD group had significantly more sSNVs compared to the control group, with neurons containing hundreds of additional sSNVs beyond those expected for age, and distributed throughout the genome
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The broadness of this distribution suggests that somatic mutations may not constitute an initial event in AD pathogenesis, but are more likely to be secondary
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Further mutational signature analysis showed that the signature C was significantly increased in the AD group, which was a C>A substitution, and was reported to be associated with oxidative damage to guanine nucleotides [3]
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The most common oxidative nucleotide damage caused by oxidative stress is 8-oxoguanine (8-oxoG), thus serving as a biomarker of cellular oxidative status and DNA damage
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As expected, the IF results targeting 8-oxoG showed significantly higher levels of 8-oxoG in AD neurons than controls, which is also consistent with the above-mentioned findings of characteristic C changes in AD groups
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Figure 1.
Schematic diagram of the experimental flow of scWGS on AD and control individual neurons.
GO analysis of mutant loci in AD and control neurons revealed that genes involved in neuronal function were enriched in sSNVs
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If sSNVs are considered together with transcriptional expression, it is necessary to distinguish whether the sSNV site is on the template strand or the untranscribed complementary strand by the template state.
The researchers found that C>A showed a clear tendency for the transcribed strand
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Somatic mutations that cause amino acid changes can cause neuronal dysfunction through multiple mechanisms, and AD neurons also exhibit more non-synonymous mutations than controls in protein-coding genes
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Furthermore, as somatic mutations accumulate in the genome, the likelihood that two deleterious exon mutations in the same gene will produce knockout cells for that gene increases exponentially, and if the rate of knockout neurons caused by sSNVs is modeled, A significant increase can be found in the AD group compared to the control group, indicating that dysfunctional neurons are more abundant in AD
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Collectively, this work reveals the signature of sSNVs in AD patient neurons by scWGS analysis of 319 neurons, and these specific mutational patterns provide clues to their cause and potential impact in AD pathogenesis as well as therapeutic targets Points such as the marked increase in signature C are consistent with reports of significant levels of oxidative damage in AD
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A major current question is how Aβ and tau deposition and genomic damage are related in AD, both of which can induce oxidative stress in cells, which may further exacerbate the effects of sSNVs and induce the emergence of more sSNVs
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Therefore, it is important to determine how protein misfolding and other known events in AD relate to the accumulation of somatic mutations in disease pathogenesis
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Original link: https://doi.
org/10.
1038/s41586-022-04640-1 Publisher: Eleven References 1.
Lodato, MA et al.
Aging and neurodegeneration are associated with increased mutations in single human neurons.
Science 359 , 555–559 (2018).
2.
Bhagwat, AS et al.
Strand-biased cytosine deamination at the replication fork causes cytosine to thymine mutations in Escherichia coli.
Proc.
Natl Acad.
Sci.
USA 113, 2176–2181 (2016) .
3.
Kucab, JE et al.
A compendium of mutational signatures of environmental agents.
Cell 177, 821–836 (2019).
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