Somatic genomic changes in single Alzheimer's disease neurons
Miller MB, Huang AY, Kim J, Zhou Z, Kirkham SL, Maury EA, Ziegenfuss JS, Reed HC et al.. Nature, 2022-04-20
Topic: Genetics and APOE
Dementia in Alzheimer's disease progresses alongside neurodegeneration 1-4 , but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations 5 at rates similar to those of dividing cells 6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation 5 . Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells 6-10 . In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation 4,11 , which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.
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APA 7th
Miller, M. B., Huang, A. Y., Kim, J., Zhou, Z., Kirkham, S. L., Maury, E. A., et al. (2022). Somatic genomic changes in single Alzheimer's disease neurons. Nature. https://doi.org/10.1038/s41586-022-04640-1
Vancouver
Miller MB, Huang AY, Kim J, Zhou Z, Kirkham SL, Maury EA, et al. Somatic genomic changes in single Alzheimer's disease neurons. Nature. 2022. doi:10.1038/s41586-022-04640-1. PMID: 35444284.
BibTeX
@article{miller2022-35444284,
author = {Miller, M. B. and Huang, A. Y. and Kim, J. and Zhou, Z. and Kirkham, S. L. and Maury, E. A. and Ziegenfuss, J. S. and Reed, H. C. and others},
title = {{Somatic genomic changes in single Alzheimer's disease neurons}},
journal = {Nature},
year = {2022},
doi = {10.1038/s41586-022-04640-1},
pmid = {35444284},
url = {https://doi.org/10.1038/s41586-022-04640-1}
}
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Key findings
- During normal ageing, neurons progressively accumulate somatic mutations 5 at rates similar to those of dividing cells 6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation 5 .
- We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns.
- Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations.
- Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function.
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Study details
- Evidence strengthLow
How this study scored 45/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 26 of the 58 points we could judge it on, which is 45 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35444284) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 26 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 26 of the 58 points we could judge it on is 45 out of 100. |
| Total | 45 / 100 | — |
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