Single-cell analysis of DNA damage, somatic mutation, and gene expression in human alzheimer?s disease brain
Ended Project Grant Awarded Last action
- Award ID
- R56AG078453
- Recipient
-
University Of Massachusetts Medical School UEI MQE2JHHJW9Q8
- Awarding agency
-
National Institute on Aging
National Institutes of Health, Department of Health and Human Services
- Obligated
- $835,825
Award facts
- Assistance listing
- 93.866 Aging Research
- Completion date
- Originally
- Place of performance
- Worcester, MA 01655, USA
Award details come from USAspending.gov.
Description
- Abstract
- Alzheimer's disease (ad) displays an age-related disease onset, but the mechanisms by which age influences disease risk are unknown. DNA damage is a hallmark of normal aging and has been implicated as a possible pathogenic mechanism in ad. We recently innovated new methods to study the genome of single neurons from the postmortem human brain. Using these novel technologies, we showed that normal neurons contain at least dozens of somatic single nucleotide variants (snvs) per genome at birth. Somatic snvs increase linearly in postmitotic neurons after birth, reaching levels in the thousands in old age. Somatic snvs can be analyzed by patterns of base-pair substitution, analogous to cancer mutations, where distinct mutational "signatures" mark tumors exposed to specific mutagens or those with deficiencies in specific DNA damage repair pathways. This analysis of our data revealed at least two neuronal mutational signatures arising in neurons from distinct sources: one related to aging generally, another related to oxidative damage in aging but especially in neurodegeneration. Analysis of the genomic distribution of neuronal somatic snvs revealed an enrichment in transcribed regions and in active enhancer elements, suggesting that somatic mutations directly impact gene expression networks. These preliminary data suggest an approach to exploring mechanisms of neuronal dysfunction in ad that may be downstream of known risk factors such as protein misfolding. In our recently published work, we showed that somatic snvs are increased in excitatory neurons of late-stage ad patients. These findings prompted several additional questions. First, at what stage of ad progression does increased somatic mutation begin? To answer this question. We will use a new and improved scwgs protocol to perform a comprehensive analysis of patterns of somatic mutation over the course of ad, including SNV and other types of variants, such as short indels and structural variants. Second, does somatic mutation result in dysregulation in gene expression? We will apply single-nucleus RNA-sequencing to ad and control brains to answer this question. Finally, how does the activity of DNA repair proteins impact the generation of somatic mutations? We will apply a quantitative approach to immunofluorescence staining for various DNA repair proteins and other marks of DNA damage on brian donors with known levels of somatic mutation to identify the root causes of mutation in the human brain. Thus, this proposal aims to understand when somatic mutations occur, what the result of those mutations are, and what caused them in the first place.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $0 | |
| Original award | $835,825 |
Quick answers
Who received award R56AG078453?
R56AG078453 was awarded to University Of Massachusetts Medical School by National Institute on Aging (National Institutes of Health) on September 1, 2023.
How much is award R56AG078453 worth?
$835,825 has been obligated on R56AG078453.
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