Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease
Open accessAbstract
Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan. While newer research has shown that DNA breaks and mutations may facilitate neuron diversity during development and neuronal function throughout life, a wealth of evidence indicates deficient DNA damage repair underlies many neurological disorders, especially age-associated neurodegenerative diseases. Recently, efforts to clarify the molecular link between DNA damage and neurodegeneration have improved our understanding of how the genomic location of DNA damage and defunct repair proteins impact neuron health. Additionally, work establishing a role for senescence in the aging and diseased brain reveals DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.
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Written from the paper’s full text.
TL;DR
This review synthesizes evidence that DNA damage contributes mechanistically to neurodegeneration through two routes: the genomic location of lesions disrupting transcription of neuronal genes, and downstream lesion-detection signaling (DDR and cytosolic DNA sensing) driving apoptosis, senescence, and neuroinflammation. It argues that DNA repair syndromes serve as proxies for aging-related neurodegeneration and that senescence biology may link DNA damage to neuroinflammation.
Key findings
- Neurons are uniquely vulnerable because they are post-mitotic (excluding error-free homologous recombination), long-lived, and transcriptionally/energetically demanding — consuming approximately 20% of the body's available oxygen, with ROS-mediated damage greatest in the nervous system.
- DNA breaks have functional roles in neurons: activity-induced DSBs occur at immediate-early gene promoters (e.g., after bicuculline stimulation, fear learning, or novel environment exposure), but recurrence at these regulatory sequences makes them vulnerable to mutation and translocation; postmitotic neurons accumulate breaks in regulatory elements associated with neuronal function.
- SSBR mutations manifest exclusively as neurodegenerative syndromes (AOA1/AOA4 from APTX/PNKP, SCAN1 from TDP1, AOA5 from XRCC1); mutant XRCC1 causes PARP1 hyperactivity, excessive poly(ADP-ribose), NAD+/ATP depletion, Parthanatos, and in mouse brain progressive cerebellar degeneration, ataxia, seizure-like activity, and dysregulated presynaptic calcium signaling.
- DNA damage links to neuroinflammation via ATM–NF-κB signaling and cGAS-STING sensing of cytosolic self-DNA; removal of senescent cells mitigates NFT burden, amyloid burden, neuronal loss, and cognitive decline in mouse models of tauopathy, AD, PD, and normal aging.
Methods
- Narrative review; no primary data collection or new experiments.
- Synthesizes literature on DDR pathways (SSB/BER, NER, DSB/NHEJ, HR), DNA repair disorders, age-associated neurodegenerative disease, and senescence/neuroinflammation.
- Discusses DNA lesion-mapping technologies (γH2AX ChIP-seq, END-seq, BLISS, SSiNGLe, LAM-HTGTS, SAR-seq, Click-Code-seq, Nick-seq, ATAC-seq) and their application to neurons.
Limitations
- Stated by the paper: the mechanistic relationship between neuroinflammation and DNA damage "has yet to be fully realized"; the utility of newer break-mapping techniques (BLISS, SSiNGLe) in neurons has yet to be evaluated; it remains to be seen whether DNA damage itself is the main inducer of senescence in each brain cell type; the concept of senescent-like phenotypes in neurons is "particularly controversial" because senescence was initially defined in cycling cells; murine ATM knockout only mildly recapitulates AT ataxia and cerebellar atrophy, limiting mechanistic work.
- Evident from the text: as a review, all conclusions rest on cited primary studies rather than new data; several key claims (e.g., neuronal cGAS-STING in HD/ALS, neuronal senescence) are described as hypotheses or early observations requiring further dissection.
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Claims the paper makes
0 of 175 cited sources checked · 0 supported · 0 flagged
- Interpretationcitation
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.”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.
“work establishing a role for senescence in the aging and diseased brain reveals DNA damage may play a central role in neuroinflammation associated with neurodegenerative disease.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
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”
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The majority of genomic injuries ultimately manifest as single-strand breaks (SSBs).
“the majority ultimately manifest in the form of single‐strand breaks (SSBs)”
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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”
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- Interpretationcitation
The genomic location of DNA damage impacts neuronal activity and degeneration.
“we are just beginning to appreciate the significance of a lesion’s genomic location in relation to its effect on neuronal activity and, ultimately, degeneration”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Neurons exhibit substantial mitochondrial respiration, consuming approximately 20% of the body's available oxygen.
“neurons exhibit substantial mitochondrial respiration, consuming approximately 20% of the body’s available oxygen”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Attwell & Laughlin, 2001 source
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- Interpretationreasoning
DNA damage may be an initiating lesion of toxicity.
“suggesting it may be an initiating lesion of toxicity”
Quote in the paperSubstantial claim - Interpretationnone given
Postmitotic neurons presumably incur the majority of their DSBs through transcriptional activity.
“postmitotic neurons presumably incur the majority of their DSBs through transcriptional activity”
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DNA damage seems to be one of the earliest indicators of neuropathology.
“In many cases, DNA damage seems to be one of the earliest indicators of neuropathology”
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A well-established link exists between DNA damage and neurodegenerative diseases.
“A well‐established link exists between DNA damage and neurodegenerative diseases.”
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ROS-mediated DNA damage is greatest in the nervous system.
“ROS‐mediated DNA damage is greatest in the nervous system”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nakamura & Swenberg, 1999
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- Interpretationreasoning
The nervous system is particularly sensitive to loss-of-function mutations in DNA repair proteins.
“The nervous system is particularly sensitive to loss‐of‐function mutations in DNA repair proteins.”
Quote in the paperSubstantial claim - Interpretationreasoning
DNA breaks' recurrence in neuron regulatory sequences makes these regions extremely vulnerable to mutation and translocation.
“while DNA breaks may serve a physiological function in learning and memory, their recurrence in neuron regulatory sequences makes these regions extremely vulnerable to mutation and translocation.”
Quote in the paperSubstantial claim - Interpretationreasoning
These features reduce the burden of DNA damage toxicity in glia.
“Combined, these features reduce the burden of DNA damage toxicity in glia.”
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Introducing a mouse to a new environment is quickly followed by the induction of DSBs in neurons.
“Even simply introducing a mouse to a new environment is quickly followed by the induction of DSBs in neurons”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Suberbielle et al, 2013, 2015
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- Interpretationcitation
Some somatic mutations may underly neurodevelopmental and neurodegenerative disease.
“work has shown that some may underly neurodevelopmental and neurodegenerative disease.”
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ATM phosphorylates downstream substrates such as H2A.X, CHK2, and p53 to initiate DSB repair, cell cycle arrest, and apoptosis.
“the protein kinase ATM phosphorylates numerous downstream substrates such as histone variant H2A.X, checkpoint kinase 2 (CHK2), and p53 to initiate DSB repair, cell cycle arrest, and apoptosis, respectively.”
Quote in the paperNot a substantial claim - Premisecitation
DNA repair mapping reveals that postmitotic neurons accumulate breaks in regulatory elements associated with neuronal function.
“DNA repair mapping reveals that postmitotic neurons do indeed accumulate breaks in regulatory elements associated with neuronal function”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Reid et al, 2021 source
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- cites Wu et al, 2021
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- Premisecitation
Somatic mutations induced by erroneous DNA damage repair or transposable elements are a common feature of neural development, giving rise to neuron diversity through genomic mosaicism.
“somatic mutations induced by erroneous DNA damage repair or transposable elements are a common feature of neural development, giving rise to neuron diversity through genomic mosaicism”
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Mutations in TDP2 result in spinocerebellar ataxia autosomal recessive 23 (SCAR23).
“mutations in TDP2 result in a rare neurological disease termed spinocerebellar ataxia autosomal recessive 23 (SCAR23)”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Zagnoli‐Vieira et al, 2018
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- cites Gómez‐Herreros et al, 2014: 2
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- cites Errichiello et al, 2020 source
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END-seq used to identify strand breaks in human iPSC-derived neurons found that enhancers are hotspots for SSBs.
“a DSB‐mapping technique known as END‐seq was recently used to identify strand breaks in human induced pluripotent stem cell (iPSC)‐derived neurons, resulting in the finding that enhancers are hotspots for SSBs”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Canela et al, 2016 source
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- cites Wu et al, 2021
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- Interpretationreasoning
The sensitivity of the nervous system to DNA repair mutations may lie in hallmarks of neuronal identity: neurons perform transcriptionally and energetically demanding functions and are post-mitotic and long-lived.
“The explanation for this sensitivity may lie in the hallmarks of neuronal identity. That is, neurons perform transcriptionally and energetically demanding cellular functions and are post‐mitotic and long‐lived.”
Quote in the paperSubstantial claim- Rests on an assumption: Neurons are post-mitotic and long-lived.
- Premisereasoning
HR can only occur in cycling cells during or following S phase.
“Because HR requires sister chromatids, this pathway can only occur in cycling cells during or following S phase.”
Quote in the paperSubstantial claim - Interpretationcitation
DNA breaks serve a functional role in neuronal activity.
“DNA breaks seem to serve a functional role in neuronal activity”
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CAG expansion in HD is dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2.
“Notably, CAG expansion has been found to be dependent upon DNA repair proteins such as OGG1, MLH1, and MSH2, whose detection of oxidized or mismatched bases in these repetitive elements could potentially elicit erroneous repair, leading to CAG expansion (Kovtun et al, 2007; Bettencourt et al, 2016; Pinto et al, 2013; Manley et al, 1999; Lee et al, 2017, 1).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Kovtun et al, 2007 source
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- cites Bettencourt et al, 2016 source
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- cites Pinto et al, 2013 source
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- Rests on an assumption: Age-dependent CAG expansion occurs in the brains of individuals with HD, gradually increasing the toxicity of the Huntington protein in the striatum.
- Interpretationreasoning
The pathogenic load of a loss-of-function mutation accelerates the development of age-associated pathology.
“the pathogenic load of a loss‐of‐function mutation accelerates the development of age‐associated pathology”
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Loss-of-function mutations in SSBR proteins have manifested exclusively as neurodegenerative syndromes.
“To date, loss‐of‐function mutations in SSBR proteins have manifested exclusively as neurodegenerative syndromes.”
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Oxidative damage-induced poly(ADP-ribose) mediates α-synuclein aggregation and consequent neurodegeneration in PD.
“oxidative damage‐induced poly(ADP‐ribose) mediates α‐synuclein aggregation and consequent neurodegeneration in PD (Kam et al, 2018)”
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- Premisecitation
The majority of DNA damage disorders typically present in early childhood, with the exception of AOA5.
“With the exception of AOA5, which seems to have manifested exclusively in adults so far (Hoch et al, 2017: 1; O’Connor et al, 2018: 1), the majority of DNA damage disorders typically present in early childhood.”
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Mutations in XRCC1 cause Ataxia with Oculomotor apraxia Type 5 (AOA5).
“Defective XRCC1 manifests in individuals as Ataxia with Oculomotor apraxia Type 5 (AOA5), another slow‐progressing neurodegenerative disease.”
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SNPs in DNA maintenance genes influence the age of onset of HD.
“Gene‐wide association studies have further identified SNPs in DNA maintenance genes that influence the age of onset in this disease (Lee et al, 2015; Moss et al, 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Whether the resulting pathologies of a DNA repair deficit are developmental or age-associated likely depends on both the brain cell type composition at the time and the selective vulnerabilities of different neuronal subtypes to different repair deficits.
“whether the resulting pathologies of a DNA repair deficit are developmental or age‐associated likely depends on both the brain cell type composition at the time and the selective vulnerabilities of different neuronal subtypes to different repair deficits.”
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Oxidative damage-induced poly(ADP-ribose) facilitates the formation of cytoplasmic TDP-43 foci in ALS.
“facilitates the formation of cytoplasmic TDP‐43 foci in ALS (McGurk et al, 2018a, 2018b)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites McGurk et al, 2018a, 2018b
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- Premisereasoning
Deficient DNA damage repair in vulnerable NPCs results in developmental abnormalities such as microcephaly.
“Deficient DNA damage repair in these vulnerable NPCs results in developmental abnormalities such as microcephaly”
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Inheritable DNA damage disorders frequently present with neurologic abnormalities.
“inheritable DNA damage disorders, which frequently present with neurologic abnormalities”
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Increased PARP1 activation and elevated poly(ADP-ribose) are observed in numerous neurodegenerative disorders and their associated animal models.
“Increased PARP1 activation and elevated poly(ADP‐ribose) has been observed in numerous neurodegenerative disorders and their associated animal models (Thapa et al, 2021; Mao & Zhang 2022).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Aberrant DNA repair may directly mediate the severity of neurodegenerative disorders such as HD.
“Aberrant DNA repair may also directly mediate the severity of neurodegenerative disorders like HD, whose toxicity is derived from the CAG trinucleotide expansion of the Huntingtin gene.”
Quote in the paperSubstantial claim- Rests on an assumption: HD toxicity is derived from the CAG trinucleotide expansion of the Huntingtin gene.
- Premisecitation
DSB marker proteins correlate with cognitive impairment in individuals with low levels of amyloid and tau pathology.
“Similarly, DSB marker proteins correlate with cognitive impairment in individuals with low levels of amyloid and tau pathology (Simpson et al, 2015).”
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- Interpretationreasoning
In DNA damage disorders with age-associated pathologies, post-mitotic neurons are likely bearing the brunt of the DNA repair deficit.
“it is likely that post‐mitotic neurons are bearing the brunt of the DNA repair deficit.”
Quote in the paperSubstantial claim - Interpretationreasoning
Erroneous DNA repair mechanisms directly influence HD severity.
“Therefore, erroneous DNA repair mechanisms also directly influence HD severity.”
Quote in the paperSubstantial claim- Rests on an assumption: HD toxicity is derived from the CAG trinucleotide expansion of the Huntingtin gene.
- Rests on an assumption: Age-dependent CAG expansion occurs in the brains of individuals with HD, gradually increasing the toxicity of the Huntington protein in the striatum.
- Premisenone given
Many DNA damage disorders are defined by age-associated pathologies such as progressive brain atrophy and peripheral neuropathy.
“many DNA damage disorders are also defined by age‐associated pathologies such as progressive brain atrophy and peripheral neuropathy.”
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DNA damage repair plays a pivotal role in neurodevelopment.
“we must acknowledge the pivotal role of DNA damage repair in neurodevelopment”
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Increased DDR foci are observed in neurons from individuals with MCI and AD compared to aged counterparts.
“Specifically, increased DDR foci are observed in neurons from individuals with mild cognitive impairment (MCI) and AD compared to aged counterparts (Shanbhag et al, 2019).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shanbhag et al, 2019 source
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- Interpretationcitation
Accumulation of SNVs at neurodegeneration risk genes could potentially increase risk of disease development.
“Accumulation of SNVs at neurodegeneration risk genes could potentially increase risk of disease development.”
Quote in the paperSubstantial claim - Interpretationreasoning
An individual devoid of DNA repair mutations must experience the progressive stress of aging to recapitulate the pathogenic load of a DNA damage disorder.
“an individual devoid of DNA repair mutations must experience the progressive stress of aging (i.e. damage accumulation, oxidative stress, declining DNA repair enzyme efficiency) in order to recapitulate the pathogenic load of a DNA damage disorder.”
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FUS activates and recruits the XRCC1-LIG3 complex to sites of oxidative DNA damage in a PARP1-dependent manner.
“and FUS activates and recruits the XRCC1‐LIG3 complex to sites of oxidative DNA damage in a PARP1‐dependent manner (Naumann et al, 2018; Wang et al, 2018a).”
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- cites Wang et al, 2018a
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- Premisecitation
Toxic aggregation of α-synuclein in the nucleus or cytosol elicits the accumulation of DSBs.
“However, toxic aggregation of α‐synuclein in the nucleus or cytosol elicits the accumulation of DSBs (Vasquez et al, 2017; Milanese et al, 2018).”
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Oxidative damage-induced poly(ADP-ribose) can mediate neuroinflammatory activity in AD.
“can mediate neuroinflammatory activity in AD (Kauppinen et al, 2011)”
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- Premisecitation
Tau deletion in the mouse brain leads to the accumulation of DSB foci in neurons.
“Tau may also play a role in DSB repair as well, as its deletion in the mouse brain leads to the accumulation of DSB foci in neurons (Violet et al, 2014; Mansuroglu et al, 2016).”
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Removal of senescent cells promotes healthy aging in mice.
“Importantly, removal of senescent cells promotes healthy aging in mice, making senescence‐associated inflammatory signaling an attractive target of therapeutic intervention for aging and age‐related disease (Tilstra et al, 2012; Childs et al, 2015; Baker et al, 2016; Ogrodnik et al, 2021).”
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Many risk genes associated with AD mediate their effects through microglia.
“Indeed, many of the risk genes associated with AD mediate their effects through microglia, the brain‐resident macrophages (Glass et al, 2010; Heneka et al, 2015; Nott et al, 2019).”
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Genome-wide profiling of DNA breaks in post-mitotic neurons has revealed that their locations are likely major mediators of their toxicity.
“To this end, genome‐wide profiling of DNA breaks in post‐mitotic neurons have revealed that their locations are likely major mediators of their toxicity.”
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- cites Wu et al, 2021
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- Premisecitation
Persistent DDR signaling in fibroblasts, bone marrow-derived macrophages, and primary monocytes elicits the senescence-associated secretory phenotype.
“Initially, induction of persistent DDR signaling in cell cultures including fibroblasts (Coppé et al, 2008; Rodier et al, 2009), bone marrow‐derived macrophages (BMDMs) (Härtlova et al, 2015), and primary monocytes (Brzostek‐Racine et al, 2011) was found to elicit the SASP (Coppé et al, 2008).”
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FUS facilitates DSB repair through its colocalization with HDAC1.
“FUS is an RNA/DNA binding protein that has been found to facilitate DSB repair through its colocalization with HDAC1 (Wy et al, 2013, 1).”
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Phosphorylation of FUS occurs in response to DSB detection by ATM and DNA-PK.
“Furthermore, phosphorylation of FUS occurs in response to DSB detection by proteins ATM and DNA‐PK (Gardiner et al, 2008; Deng et al, 2014)”
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Over time, erroneous repair of breaks in regulatory regions of neuronal genes could lead to disruptive translocations, mutations, and genomic instability.
“It follows that while these breaks may be functionally relevant, over time, their erroneous repair could lead to disruptive translocations, mutations, and genomic instability.”
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The SASP induced by persistent DDR signaling is at least partially ATM-dependent.
“This secretory profile was found to be at least partially ATM‐dependent, implying the importance of DSB repair specifically in immune activation (Rodier et al, 2009; Brzostek‐Racine et al, 2011).”
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- cites Brzostek‐Racine et al, 2011
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- Interpretationreasoning
Senescence is considered a potential driver of neuroinflammation and neurodegeneration.
“Thus, senescence is now considered as a potential driver of neuroinflammation and neurodegeneration.”
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In AT fibroblasts, NF-kB is activated in an ATM-dependent manner following treatment with a radiomimetic, ionizing radiation, or topoisomerase inhibitor.
“Previous work with AT fibroblasts had shown that the canonical immune transcription factor NF‐kB is activated in an ATM‐dependent manner following treatment with a radiomimetic, ionizing radiation, or topoisomerase inhibitor (Lee et al, 1998; Piret et al, 1999; Li et al, 2001).”
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Many genes that encode the building blocks of neurodegenerative proteinopathies play a role in the DNA damage response.
“In addition to PARP1 activity, many genes that encode the building blocks of neurodegenerative proteinopathies have been found to play a role in DDR as well.”
Quote in the paperSubstantial claim - Interpretationreasoning
DNA breaks are a mechanism of neurodegenerative disease.
“While these findings have firmly established DNA breaks as a mechanism of neurodegenerative disease, the mechanisms by which break location may contribute to disease progression are not well described.”
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Neuroinflammation has emerged as a core feature and mechanism of neurodegenerative disease.
“In addition to DNA damage, neuroinflammation has emerged as a core feature and mechanism of neurodegenerative disease.”
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TDP-43 is directly involved in NHEJ through its recruitment and stabilization of the XRCC4-LIG4 complex at DSBs.
“Recently, TDP‐43 was also found to be directly involved in NHEJ through its recruitment and stabilization of the XRCC4‐LIG4 complex at DSBs (Guerrero et al, 2019; Mitra et al, 2019).”
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Postmitotic neurons harbor SSBs and other forms of breaks in the regulatory regions of genes that modulate synaptic plasticity and neuronal function.
“As described earlier, the use of nucleoside analog incorporation to map DNA repair has led to the observation that postmitotic neurons harbor SSBs and other forms of breaks in the regulatory regions of genes that modulate synaptic plasticity and neuronal function (Reid et al, 2021; Wu et al, 2021).”
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- cites Wu et al, 2021
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- Premisecitation
Observations of senescent-like phenotypes in neurons have been reported.
“Nevertheless, observations of senescent‐like phenotypes in neurons have been reported for quite some time.”
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The NLRP3 inflammasome senses cytosolic DNA to activate cleavage of pro-IL1b and pro-IL18 via Caspase I to elicit their secretion.
“An additional mechanism of cytosolic DNA‐mediated inflammation is through the NLRP3 inflammasome, which senses cell stressors (such as cytosolic DNA) to activate the cleavage of pro‐1L1b and pro‐IL18 via Caspase I to elicit their secretion.”
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Senescent astrocytes are modulators of PD pathology.
“Additionally, senescent astrocytes have been identified as modulators of PD pathology (Chinta et al, 2018).”
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DSBs were considered the major driver of senescence-associated phenotypes in aged mouse neurons because p21 knockout mitigated their enrichment.
“Here, DSBs were considered the major driver of these senescence‐associated phenotypes because knock‐out of p21, a protein activated by p53 to initiate DSB‐induced cell cycle arrest, was able to mitigate their enrichment.”
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AGS is caused by mutations in genes that regulate nucleic acid metabolism.
“AGS is caused by mutations in genes that regulate nucleic acid metabolism.”
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Sequencing cytosolic DNA fragments from ATM-deficient microglia revealed that most were derived from nuclear DNA as intergenic repetitive elements, suggesting the source of cytosolic DNA may not be random.
“Interestingly, sequencing the cytosolic DNA fragments from these microglia revealed that most were derived from the nuclear DNA as intergenic repetitive elements, suggesting that the source of cytosolic DNA may not be random (Song et al, 2021).”
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The interplay between NF-kB and p53 strongly influences cellular fate following DNA damage accumulation.
“Thus, the interplay between NF‐kB and p53 strongly influence cellular fate following DNA damage accumulation (Karin & Lin, 2002).”
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Following DSB induction, activated ATM couples with protein intermediates leading to its cytoplasmic transport and downstream activation of NF-kB.
“Subsequent studies confirmed that following DSB induction, activated ATM couples with a number of protein intermediates leading to its cytoplasmic transport and downstream activation of NF‐kB (Hinz et al, 2010; Wu et al, 2010; Miyamoto, 2011).”
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Microglial NLRP3 is a major driver of amyloid beta and tau toxicity in AD.
“In particular, microglial NLRP3 has been shown to be a major driver of amyloid beta and tau toxicity in AD, suggesting its activation has important implications for disease progression (Halle et al, 2008; Venegas et al, 2017; Ising et al, 2019).”
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Removal of senescent microglia from aged mice improves cognition.
“Finally, removal of senescent microglia from aged mice has been found to improve cognition (Ogrodnik et al, 2021).”
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- Premisenone given
DNA damage accumulates in neurons early in AD.
“Because DNA damage accumulates in neurons early on in AD, and because it is also a primary driver of senescence, it is worth hypothesizing that DNA lesions mediate neurodegeneration at least in part through neuronal senescence, although senescence in other cell types clearly also plays important roles in neurodegeneration.”
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Re-analysis of transcriptional data from AD brain tissue showed that neurons with high tau were enriched for signatures of DNA damage and senescence.
“This dataset was later re‐analyzed to show that neurons with high levels of tau were enriched for signatures of DNA damage and senescence (Dunckley et al, 2006; Musi et al, 2018).”
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ATM-deficient microglia accumulate cytosolic DNA, activating the cGAS-STING pathway to elicit pro-inflammatory and neurotoxic signals.
“For example, ATM‐deficient microglia have been shown to accumulate cytosolic DNA, thus activating the cGAS‐STING pathway to elicit pro‐inflammatory and neurotoxic signals (Quek et al, 2017; Song et al, 2019).”
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In aged mouse brain, neurons show pathological features described as senescence, including increased DSBs, lipid peroxidation, and senescent-associated β-galactosidase staining.
“As early as 2012, the term “senescence” was used to describe pathological features of neurons in the aged mouse brain, including increased DSBs, lipid peroxidation, and senescent‐associated β‐galactosidase staining (Jurk et al, 2012).”
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In RNASEH2 murine models of AGS, cGAS-STING sensing of micronuclei causes type I IFN signaling.
“Accordingly, RNASEH2 murine models of AGS reveal that CGAS‐STING sensing of micronuclei is the cause for type I IFN signaling in this disease (Mackenzie et al, 2016, 2017; Pokatayev et al, 2016).”
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Senescent-like phenotypes in neurons have been noted in other models of aging and neurodegeneration.
“Senescent‐like phenotypes in neurons have also been noted in other models of aging and neurodegeneration (Chow et al, 2019; Moreno‐Blas et al, 2019).”
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Deficits in RNASEH2 comprise more than half of AGS diagnoses.
“For example, deficits in RNASEH2, an enzyme responsible for removing ribonucleotides from DNA and resolving R‐loops, comprise more than half of AGS diagnoses (Crow & Manel, 2015).”
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- Premisecitation
Single-nucleus RNA sequencing of AT cerebella reveals that microglial activation likely precedes neuronal degeneration.
“Recent single‐nucleus RNA sequencing of AT cerebella reveals that microglial activation likely precedes neuronal degeneration, further emphasizing the role of microglia in ATM‐mediated neuropathology (Lai et al, 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lai et al, 2021
Not checked in the free run.
- Interpretationreasoning
Dysregulated NF-kB signaling in neurons could be a key mechanism linking DNA damage accumulation, altered synaptic function, and disease progression.
“Thus, dysregulated NF‐kB signaling in neurons could be a key mechanism linking DNA damage accumulation, altered synaptic function, and disease progression.”
Quote in the paperSubstantial claim - Interpretationnone given
Emerging evidence suggests that many cell types in the brain, including astrocytes, microglia, oligodendrocytes, and neurons, may mediate the cytotoxicity of DNA damage through senescence-associated signaling.
“While these are mechanisms specific to neurons, emerging evidence also suggests that many cell types in the brain, including astrocytes, microglia, oligodendrocytes, and neurons, may mediate the cytotoxicity of DNA damage through senescence‐associated signaling.”
Quote in the paperSubstantial claim - Premisecitation
Observations of neuron-derived immune signaling at early stages of neurodegenerative disease indicate that this may play a role in disease progression.
“Indeed, observations of neuron‐derived immune signaling at early stages of neurodegenerative disease indicate that this may play a role in disease progression (Dutta et al, 2020; Welikovitch et al, 2020).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
NF-kB plays neuron-specific roles in learning and memory.
“Intriguingly, the inflammatory transcription factor NF‐kB also plays neuron‐specific roles in learning and memory.”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Murine models of DNA damage and DNA break mapping techniques have allowed identification of how DNA damage may regulate expression of genes essential for neuronal function and how this might lead to dysfunction later in life.
“The utilization of murine models of DNA damage and DNA break mapping techniques have allowed us to identify how DNA damage may regulate the expression of genes essential for neuronal function, and how this might lead to dysfunction later in life.”
Quote in the paperSubstantial claim - Premisecitation
Inhibition of NF-kB signaling specifically in neurons impairs synaptic plasticity and synaptogenesis.
“Inhibition of NF‐kB signaling specifically in neurons impairs synaptic plasticity and synaptogenesis (O’Mahony et al, 2006; Boersma et al, 2011).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Neuron-derived inflammatory signaling is a critical feature of the antiviral response to neurotropic viral infections.
“However, work examining the immune response to neurotropic viral infections reveals neuron‐derived inflammatory signaling is a critical feature of the antiviral response (Klein et al, 2005; Chakraborty et al, 2010; Di Liberto et al, 2018).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationcitation
NF-kB is critical for homeostatic neuronal function.
“These data suggest that on top of its function as a pro‐survival and pro‐inflammatory transcription factor, NF‐kB is also critical for homeostatic neuronal function (Kaltschmidt & Kaltschmidt, 2009).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kaltschmidt & Kaltschmidt, 2009 source
Not checked in the free run.
- Premisecitation
Suppression of neuronal NF-kB in vivo renders neurons more susceptible to kainic acid-induced neurotoxicity.
“Furthermore, suppression of neuronal NF‐kB in vivo renders neurons more susceptible to kainic acid‐induced neurotoxicity (Fridmacher et al, 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fridmacher et al, 2003 source
Not checked in the free run.
- Premisecitation
The protein machinery required to detect cytosolic DNA such as STING is reported to be low in neurons compared to glial cells.
“Indeed, the protein machinery required to detect cytosolic DNA such as STING is reported to be low in neurons compared to glial cells (Mathur et al, 2017; Song et al, 2019).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
DNA damage can elicit neuron dysfunction broadly through two distinct mechanisms.
“Regardless, it is clear that DNA damage can elicit neuron dysfunction broadly through two distinct mechanisms.”
Quote in the paperSubstantial claim - Interpretationreasoning
The location of a DNA lesion has a significant impact on transcriptional mechanisms required for normal cell function.
“First, the location of the lesion has a significant impact on transcriptional mechanisms required for normal cell function.”
Quote in the paperSubstantial claim - Interpretationnone given
Downstream signaling pathways of lesion detection, whether through DDR or cytosolic nucleic acid sensing, can elicit apoptotic or inflammatory signaling that leads to neurotoxicity.
“Second, the downstream signaling pathways of lesion detection, whether they be through DDR or cytosolic nucleic acid sensing, can elicit apoptotic or inflammatory signaling that lead to neurotoxicity.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 9
- May combine two claims. 36
Probably not a substantial claim: may not pass S4 (based).
Interpretationnone givenNeurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan.
“Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan.”
Quote in the paperNot a substantial claim- Rests on an assumption: Neurons are post-mitotic and long-lived.
May combine two claims.
PremisecitationApoptosis, senescence, and uncontrolled cell division are hallmarks of age-associated disease.
“all of which are hallmarks of age‐associated disease”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationJust one DSB can induce cell cycle arrest and subsequent apoptosis.
“it is popularly cited that just one DSB can induce cell cycle arrest and subsequent apoptosis”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Huang et al, 1996 source
Not checked in the free run.
May combine two claims.
PremisecitationDefective 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”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisenone givenSSBs may form DSBs through collision with the transcriptional machinery and replication forks, or through close proximity to another SSB.
“SSBs may form DSBs through their collision with the transcriptional machinery and replication forks, or through their close proximity to another SSB.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Cannan & Pederson, 2016 source
Not checked in the free run.
May combine two claims.
Premisenone givenSSBs are more common than DSBs, but DSBs have higher potential for toxicity.
“While SSBs are the more common form of DNA damage, double‐strand breaks (DSBs) have the higher potential for toxicity.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDSBs are directly generated by transcription, whereby TOP2 induces transient DSBs to relieve torsional stress and facilitate gene expression.
“DSBs are also directly generated by transcription (Cannan & Pederson, 2016), whereby topoisomerase II (TOP2) induces transient DSBs to relieve torsional stress and facilitate gene expression.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cannan & Pederson, 2016 source
Not checked in the free run.
May combine two claims.
PremisecitationDSBs play important roles in cell physiology, including T-cell receptor and antibody diversity, chromosomal recombination during meiosis, and immediate early gene expression in neurons.
“DSBs are required for T‐cell receptor and antibody diversity, chromosomal recombination during meiosis, and in the case of neurons, assist in the expression of immediate early genes”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisenone givenPARP1 senses both SSBs and DSBs, rapidly generating PAR chains to recruit DNA repair proteins and relax chromatin at break sites.
“PARP1 senses both SSBs and DSBs, rapidly generating poly(ADP‐ribose) (PAR) chain scaffolds (PARylation) on itself and other target proteins to recruit DNA repair proteins and relax chromatin at break sites.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisereasoningNHEJ operates in all phases of the cell cycle and is the only DSB repair pathway available to post-mitotic cells.
“NHEJ operates in all phases of the cell cycle and thus is the only DSB repair pathway available to post‐mitotic cells.”
Quote in the paperSubstantial claimMay combine two claims.
Premisereasoningalt-NHEJ and SSA are inherently error-prone.
“Both alt‐NHEJ and SSA are inherently error‐prone”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenPhosphorylation of H2A.X (γH2AX) by ATM flanks DSB sites more than 500 kb upstream and downstream to form γH2AX foci.
“phosphorylation of H2A.X (γH2AX) by ATM is a critical post‐translational modification, flanking DSB sites more than 500 kb upstream and downstream to form γH2AX foci”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationStimulating primary neurons with bicuculline or subjecting mice to fear learning results in the induction of DSBs at the promoters of immediate-early genes.
“Stimulating primary neurons with bicuculline or subjecting mice to fear learning results in the induction of DSBs at the promoters of immediate‐early genes”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenDNA damage in glia plays demonstrable roles in neurodegeneration.
“DNA damage in glia plays demonstrable roles in neurodegeneration, as we will discuss later.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenPARP1 and ATM are two major sensors of SSBs and DSBs.
“Poly(ADP‐ribose) polymerase 1 (PARP1) and Ataxia telangectasia mutated (ATM) are two major sensors of SSBs and DSBs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenHR is an error-free method of DSB repair by which resected DNA strands utilize their sister chromatid as a template.
“HR is considered an error‐free method of DSB repair by which resected DNA strands utilize their sister chromatid as a template for DNA synthesis.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationDSB hotspots reside in long genes that are important for neuronal function and are risk factors for autism spectrum disorder and schizophrenia.
“DSB hotspots reside in long genes that are important for neuronal function and are risk factors for autism spectrum disorder and schizophrenia”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Wei et al, 2016, 2018
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Wang et al, 2020 source
Not checked in the free run.
May combine two claims.
PremisecitationSomatic single nucleotide variations (SNVs) increase with age and are enriched in genes that regulate tau phosphorylation in hippocampal tissue from individuals with Alzheimer's disease.
“a study performing whole exome sequencing of hippocampal tissue from individuals with Alzheimer’s disease (AD) revealed that somatic single nucleotide variations (SNVs) increase with age and are enriched in genes that regulate tau phosphorylation”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Park et al, 2019 source
Not checked in the free run.
May combine two claims.
PremisereasoningCompared to neurons, glial cells are replaceable, have lower energy requirements, and in some cases are able to re-enter the cell cycle, thus facilitating DNA repair.
“compared to neurons, glial cells are replaceable, have lower energy requirements, and, in some cases, are able to re‐enter the cell cycle, thus facilitating DNA repair.”
Quote in the paperSubstantial claim- Rests on an assumption: Glial cells are replaceable, have lower energy requirements, and can re-enter the cell cycle.
May combine two claims.
InterpretationreasoningThe consequence of neuronal features is elevated ROS byproducts, exclusion of error-free HR repair, age-associated decline in DNA repair enzyme efficiency, and an overall increased chance of somatic mutation.
“The consequence of these features is elevated ROS byproducts, exclusion of error‐free HR repair, age‐associated decline in DNA repair enzyme efficiency, and an overall increased chance of somatic mutation.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
InterpretationreasoningErroneous DSB repair could lead to mutations that result in transcriptomic dysfunction, which could manifest at the cellular level as impaired synaptic signaling.
“erroneous DSB repair could lead to mutations that result in transcriptomic dysfunction, which could further manifest at the cellular level as impaired synaptic signaling.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationSingle-cell whole genome sequencing has revealed that somatic SNVs located near neuronal genes increase with age in human neurons, presumably due to errors in BER, NER, and transcription-associated repair.
“single‐cell whole genome sequencing has revealed that somatic SNVs located near neuronal genes increase with age in human neurons, presumably due to errors in BER, NER, and transcription‐associated repair (Fig 2) (Lodato et al, 2015, 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lodato et al, 2015, 2018
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisenone givenAOA1 and AOA4 are caused by mutations in APTX and PNKP respectively.
“Ataxia with Oculomotor Apraxia types 1 and 4 (AOA1, AOA4) are caused by mutations in DNA end‐processing enzymes Aprataxin (APTX) and Polynucleotide Kinase 3′‐Phosphatase (PNKP) respectively.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationSCAN1 is caused by defective TDP1 and is characterized by peripheral neuropathy.
“SCAN1, caused by defective TDP1, is a similar neurodegenerative syndrome additionally characterized by peripheral neuropathy”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Takashima et al, 2002 source
Not checked in the free run.
- cites El‐Khamisy et al, 2005
Not checked in the free run.
May combine two claims.
Premisecitation8oxoG can repress gene transcription through multiple mechanisms, including blocking transcription factor binding, recruiting chromatin remodelers that methylate gene promoters, and erroneous BER that can result in single nucleotide variations.
“8oxoG is capable of repressing gene transcription through many mechanisms, including blocking transcription factor binding (Ghosh & Mitchell, 1999; Moore et al, 2016), recruiting chromatin remodelers that result in the methylation of gene promoters(Wang et al, 2018b; Xia et al, 2017, 4), and erroneous repair through BER, which could result in single nucleotide variations (SNVs).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIncreased levels of both SSBs and DSBs are documented in AD, HD, PD, and ALS, and their accumulation correlates with important milestones in disease progression.
“A plethora of studies document increased levels of both SSBs and DSBs in AD, HD, PD, and ALS (Mullaart et al, 1990; Adamec et al, 1999; McKinnon, 2013, 2017; Madabhushi et al, 2014; Alt & Schwer, 2018; Shanbhag et al, 2019; Thadathil et al, 2021), and their accumulation seem to correlate with important milestones in disease progression.”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationIncreased ROS and DSBs are documented in neurons derived from sporadic AD patient fibroblasts, indicating that age-dependent features of genomic instability are recapitulated in human in vitro models of disease.
“More recently, increased ROS and DSBs have also been documented in neurons derived directly from sporadic AD patient fibroblasts, indicating that age‐dependent features of genomic instability are recapitulated in human in vitro models of disease (Mertens et al, 2021).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mertens et al, 2021 source
Not checked in the free run.
May combine two claims.
PremisecitationDNA damage is a potent activator of inflammatory signaling and senescence.
“DNA damage is a potent activator of inflammatory signaling and senescence (Coppé et al, 2008; Rodier et al, 2009; Brzostek‐Racine et al, 2011; Härtlova et al, 2015).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationSenescent-like brain cells are identified in murine models of AD and tauopathy, and their removal via senolytic drugs mitigates pathology and improves cognition.
“More recently, researchers have identified senescent‐like brain cells in murine models of AD and tauopathy, and their removal via senolytic drugs seems to mitigate pathology and improve cognition (Bussian et al, 2018; Musi et al, 2018; Zhang et al, 2019; Ogrodnik et al, 2021).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitationα-synuclein binds double-strand DNA and facilitates NHEJ in homeostasis.
“Finally, α‐synuclein, whose cytoplasmic aggregation is a hallmark of PD, is able to bind double‐strand DNA and facilitate NHEJ in homeostasis (Schaser et al, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Schaser et al, 2019 source
Not checked in the free run.
May combine two claims.
PremisecitationHuntington protein may play a role in DNA damage detection, potentially serving as a scaffold for ATM at sites of oxidized DNA and for ATXN3 and PNKP at sites of transcription-coupled DNA break repair.
“The Huntington protein may also play a role in DNA damage detection, potentially serving as a scaffold for ATM at sites of oxidized DNA (Maiuri et al, 2017), and ATXN3 and PNKP at sites of transcription‐coupled DNA break repair (Gao et al, 2019).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Maiuri et al, 2017
Not checked in the free run.
- cites Gao et al, 2019
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe mechanistic link between DNA damage and senescence has already been defined in detail.
“Importantly, while not well‐studied in the context of the degenerating brain, the mechanistic link between DNA damage and senescence has already been defined in great detail (d’Adda di Fagagna, 2008; Miyamoto, 2011; Li & Chen, 2018).”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationDNA damage can evoke type-I interferon signaling in AT cells due to accumulation of cytosolic DNA fragments, suggesting that activation of inflammatory signaling via DNA damage can occur independent of the DSB DDR.
“Interestingly, a subsequent study revealed that DNA damage can also evoke type‐I interferon signaling in AT cells due to the accumulation of cytosolic DNA fragments, suggesting activation of inflammatory signaling via DNA damage can occur independent of the DSB DDR (Härtlova et al, 2015).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Härtlova et al, 2015 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningDNA damage has direct molecular links to senescence-associated inflammatory signaling, both through DDR pathway activation and the mis-localization of DNA itself.
“Therefore, DNA damage has direct molecular links to senescence‐associated inflammatory signaling, both through DDR pathway activation and the mis‐localization of DNA itself (Fig 3).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningDifferent phenotypes of DNA damage response deficits are mediated by different pathways, which may have preferential function in different cell types.
“This indicates that different phenotypes of DNA damage response deficits are mediated by different pathways, which may have preferential function in different cell types.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTLR9 binds double-stranded DNA in endosomes, recruits MYD88 to activate NFkB, and stimulates expression of inflammatory cytokines.
“This includes TLR9 (Toll‐like receptor 9), which binds to double‐stranded DNA engulfed in endosomes, particularly bacterial DNA or mtDNA. This recruits adaptor protein MYD88 (myeloid differentiation primary response 88) to activate NFκB and stimulate the expression of inflammatory cytokines.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Miller et al, 2021 source
Not checked in the free run.
May combine two claims.
PremisecitationRemoval of senescent cells in the brain mitigates NFT burden, amyloid burden, neuronal loss, and cognitive decline in mouse models of tauopathy, AD, PD, and normal aging.
“It has since been shown that removal of senescent cells in the brain mitigates neurofibrillary tangle (NFT) burden, amyloid burden, neuronal loss, and cognitive decline in mouse models of tauopathy (Bussian et al, 2018; Musi et al, 2018), AD (Zhang et al, 2019), PD (Chinta et al, 2018), and normal aging (Ogrodnik et al, 2021).”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
PremisecitationMicroglia, astrocytes, and neurons display senescent-like phenotypes in Tau P301S mice and have been proposed as drivers of cognitive decline and neurodegeneration.
“For example both microglia (Bussian et al, 2018), astrocytes (Bussian et al, 2018), and neurons (Musi et al, 2018) have been found to display senescent‐like phenotypes in Tau P301S mice, and have been proposed as drivers of cognitive decline and neurodegeneration.”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
PremisecitationSenescent-like phenotypes are identified in oligodendrocyte precursor cells in APP/PS1 mice, and their removal mitigates amyloid load and cognitive decline.
“Senescent‐like phenotypes have also been identified in oligodendrocyte precursor cells (OPCs) in APP/PS1 mice, and their removal has been shown to mitigate amyloid load and cognitive decline (Zhang et al, 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhang et al, 2019 source
Not checked in the free run.
May combine two claims.
PremisecitationIn AGS, DDR-mediated activation of p53, not cGAS-STING, causes neuron cell death, although increased micronuclei and R-loops are observed in astrocytes.
“However, recent work investigating the cause of AGS neurotoxicity revealed that it is the DDR‐mediated activation of p53, not CGAS‐STING, that causes neuron cell death, although increased micronuclei and R‐loops were observed in astrocytes (Aditi et al, 2021).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Aditi et al, 2021
Not checked in the free run.
Probably not a substantial claim: may not pass S4 (based).
Premisenone givenDNA damage is a well-established source of inflammatory signaling.
“Importantly, as DNA damage is a well‐established source of inflammatory signaling, this uncovers a previously unstudied aspect of neuronal response to DNA damage.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationNeuronal cGAS-STING is activated in models of HD and ALS, suggesting that toxic protein aggregates may stimulate DNA release to initiate NFκB activation in neurons.
“Notably, neuronal cGAS‐STING has been shown to be activated in models of HD and ALS, suggesting that toxic protein aggregates may stimulate DNA release (mitochondrial or genomic) to initiate NFκB activation in neurons (Sharma et al, 2020; Yu et al, 2020).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Sharma et al, 2020 source
Not checked in the free run.
- cites Yu et al, 2020
Not checked in the free run.
May combine two claims.
InterpretationreasoningThe detection of viral nucleic acids utilizes the same cGAS-STING pathway as detection of self-DNA in senescent cells, suggesting that the mechanism of innate immune signaling in DSB-bearing neurons may be significant.
“The detection of viral nucleic acids utilizes the same cGAS‐STING pathway as that described for detection of self‐DNA within the cytosol of senescent cells, suggesting that the mechanism of innate immune signaling in DSB‐bearing neurons may be of some significance.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Neurons are post-mitotic and long-lived.
“Post‐mitotic neurons are the basic cellular unit of the nervous system.”
“neurons perform transcriptionally and energetically demanding cellular functions and are post‐mitotic and long‐lived.”
The paper relies on this without support.
Glial cells are replaceable, have lower energy requirements, and can re-enter the cell cycle.
“compared to neurons, glial cells are replaceable, have lower energy requirements, and, in some cases, are able to re‐enter the cell cycle, thus facilitating DNA repair.”
The paper relies on this without support.
Most mutations are likely neutral.
“While most mutations are likely to be neutral”
The paper relies on this without support.
HD toxicity is derived from the CAG trinucleotide expansion of the Huntingtin gene.
“Aberrant DNA repair may also directly mediate the severity of neurodegenerative disorders like HD, whose toxicity is derived from the CAG trinucleotide expansion of the Huntingtin gene.”
The paper relies on this without support.
Age-dependent CAG expansion occurs in the brains of individuals with HD, gradually increasing the toxicity of the Huntington protein in the striatum.
“Specifically, age‐dependent CAG expansion occurs in the brains of individuals with HD, gradually increasing the toxicity of the Huntington protein in the striatum.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Accumulation of DNA damage can lead to a senescence-like state in neurons and has been implicated in the progression of AD.
“accumulation of DNA damage can lead to a senescence-like state in neurons and has been implicated 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 [123]
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- Lai J, Kim J, Jeffries AM, Tolles A, Chittenden TW, Buckley PG, Yu TW, Lodato MA, Lee EA (2021) Single‐nucleus transcriptomic analyses reveal microglial activation underlying cerebellar degeneration in Ataxia Telangiectasia. https://doi.org/10.1101/2021.09.09.459619 [PREPRINT] · DOI
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- Authors
- Welch, G., & Tsai, L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Tsai, Li‐Huei
- Venue
- The EMBO Reports
- Published
- 2022-05-02
- Volume
- 23
- Issue
- 6
- Pages
- e54217-e54217
- ISSN
- 1469-221X (ISSN-L)
- 1469-3178
- PMC
- PMC9171412
- OpenAlex
- W4225288591
- Semantic Scholar
- 2d78ba2004dfe676ffd6931eb4f23964f7f7c921
- Cited by
- 129
- References
- 183
- Citations by year
- 2026: 22 · 2025: 36 · 2024: 42 · 2023: 25 · 2022: 4
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- EMBO Reports (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- 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, neurotoxicity, neurodegenerative diseases, DNA repair, DNA strand breaks, DNA mutations, neuronal aging, cellular senescence, neuroinflammation, age-related neurodegeneration
- MeSH terms
- Aging, DNA Damage, DNA Repair, Humans, Neurons, Neurodegenerative Diseases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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