DNA damage and its links to neurodegeneration
Open accessAbstract
The integrity of our genetic material is under constant attack from numerous endogenous and exogenous agents. The consequences of a defective DNA damage response are well studied in proliferating cells, especially with regards to the development of cancer, yet its precise roles in the nervous system are relatively poorly understood. Here we attempt to provide a comprehensive overview of the consequences of genomic instability in the nervous system. We highlight the neuropathology of congenital syndromes that result from mutations in DNA repair factors and underscore the importance of the DNA damage response in neural development. In addition, we describe the findings of recent studies, which reveal that a robust DNA damage response is also intimately connected to aging and the manifestation of age-related neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis.
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Studies using post-mortem human brain samples show that neurons, astrocytes, and oligodendrocytes accumulate DNA double-strand breaks (DSBs) early in the progression of AD.
“Studies using post-mortem human brain samples show that neurons, astrocytes, and oligodendrocytes accumulate DNA double-strand breaks (DSBs) early in the progression of AD”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [2]
Neurons start accumulating DSBs early in the progression of AD.
“Neurons start accumulating DSBs early in the progression of AD”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [2]
Deficient DNA damage repair underlies many neurological disorders, especially age-associated neurodegenerative diseases.
“a wealth of evidence indicates deficient DNA damage repair underlies many neurological disorders, especially age‐associated neurodegenerative diseases.”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2014
DNA damage and defective DDR push cellular fate toward apoptosis, senescence, or uncontrolled cell division.
“These insults ultimately push cellular fate toward apoptosis, senescence, or uncontrolled cell division”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2014
Defective DDR pathways can result in toxic genomic rearrangements, transcriptional dysregulation, and the accumulation of unrepaired lesions.
“Defective DDR pathways can result in toxic genomic rearrangements, transcriptional dysregulation, and the accumulation of unrepaired lesions”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2014
Apoptosis, senescence, and uncontrolled cell division are hallmarks of age-associated disease.
“all of which are hallmarks of age‐associated disease”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2014
Reactive oxygen species (ROS) attack DNA to form oxidized bases and abasic sites.
“reactive oxygen species (ROS), which attack DNA to form oxidized bases and abasic sites”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2014
The majority of genomic injuries ultimately manifest as single-strand breaks (SSBs).
“the majority ultimately manifest in the form of single‐strand breaks (SSBs)”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Madabhushi et al, 2014
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Transcription Blockage by DNA Damage in Nucleotide Excision Repair-Related Neurological Dysfunctions
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Recent advances in understanding the mechanisms determining longevity
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- Authors
- Madabhushi, R., Pan, L., & Tsai, L.-H.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Tsai, Li-Huei
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 83
- Issue
- 2
- Pages
- 266-282
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5564444
- OpenAlex
- W2080053685
- Cited by
- 654
- References
- 151
- Citations by year
- 2026: 55 · 2025: 53 · 2024: 65 · 2023: 55 · 2022: 66 · 2021: 70 · 2020: 78 · 2019: 69 · 2018: 46 · 2017: 28 · 2016: 35 · 2015: 28 · 2014: 6
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Glenn Foundation for Medical Research
- National Institute on Aging (R01AG046174)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- DNA damage response, neurodegeneration, genomic instability, DNA repair, congenital syndromes, neural development, aging, Alzheimer's disease, amyotrophic lateral sclerosis, nervous system
- MeSH terms
- Aging, DNA Damage, DNA Repair, Humans, Nerve Degeneration, Neurons, Neurodegenerative Diseases
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