Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease

In the paper

“all of which are hallmarks of age‐associated disease”

What the sources say

• Not checked yetcites Hoeijmakers, 2009 source
• Partly supported

  The Introduction (page unavailable) links DNA damage to cell death, senescence, aging, and cancer, which supports a general connection to the processes named. It does not identify apoptosis, senescence, and uncontrolled cell division collectively as hallmarks of age-associated disease; uncontrolled cell division is not stated in the relevant passage. (LLM, conf=0.82)

  cites Madabhushi et al, 2014 sourceExperimental — accuracy not yet measured
• Not checked yetcites Chow & Herrup, 2015 source

In the paper

“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).”

What the sources say

• Partly supported

  The opening summary reports senescent astrocytes and microglia in a PS19 mouse model of tauopathy, and says genetic clearance prevented pathology and preserved cognitive function. The pharmacological-intervention passage reports that the senolytic ABT263 attenuated tau phosphorylation, but does not report improved cognition from drug treatment. This paper does not establish the claim for a murine AD model. (LLM, conf=0.88)

  cites Bussian et al, 2018 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Results report senescence-like features in tau-pathology mouse models and reduced NFT burden and brain atrophy after treatment with the senolytics dasatinib and quercetin. The Results describe MRI, histopathology, and cerebral blood-flow outcomes, but do not report a cognitive improvement; the paper only notes that blood flow is associated with cognitive impairment. (LLM, conf=0.88)

  cites Musi et al, 2018 sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports senescent OPCs in APP/PS1 AD mice and says senolytic treatment reduced Aβ pathology and improved learning and memory. It also reports senescent glial cells in tau-mutant mice and describes the studies together as showing benefits from clearing senescent cells, while distinguishing genetic clearance from senolytic-drug treatment. (LLM, conf=0.90)

  cites Zhang et al, 2019 source

In the paper

“Neurons are highly susceptible to DNA damage accumulation due to their large energy requirements, elevated transcriptional activity, and long lifespan.”

In the paper

“it is popularly cited that just one DSB can induce cell cycle arrest and subsequent apoptosis”

What the sources say

• Not checked yetcites Huang et al, 1996 source

In the paper

“Defective DDR pathways can result in toxic genomic rearrangements, transcriptional dysregulation, and the accumulation of unrepaired lesions”

What the sources say

• Not checked yetcites Hoeijmakers, 2009 source
• Not checked yetcites Madabhushi et al, 2014 source
• Not checked yetcites Chow & Herrup, 2015 source

In the paper

“SSBs may form DSBs through their collision with the transcriptional machinery and replication forks, or through their close proximity to another SSB.”

What the sources say

• Not checked yetcites Cannan & Pederson, 2016 source

In the paper

“While SSBs are the more common form of DNA damage, double‐strand breaks (DSBs) have the higher potential for toxicity.”

In the paper

“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.”

What the sources say

• Not checked yetcites Cannan & Pederson, 2016 source

In the paper

“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”

What the sources say

• Not checked yetcites Suberbielle et al, 2013 source
• Not checked yetcites Madabhushi et al, 2015 source
• Not checked yetcites Alt & Schwer, 2018 source

In the paper

“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.”

In the paper

“NHEJ operates in all phases of the cell cycle and thus is the only DSB repair pathway available to post‐mitotic cells.”

In the paper

“Both alt‐NHEJ and SSA are inherently error‐prone”

In the paper

“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”

In the paper

“Stimulating primary neurons with bicuculline or subjecting mice to fear learning results in the induction of DSBs at the promoters of immediate‐early genes”

What the sources say

• Not checked yetcites Madabhushi et al, 2015 source
• Not checked yetcites Stott et al, 2021 source

In the paper

“DNA damage in glia plays demonstrable roles in neurodegeneration, as we will discuss later.”

In the paper

“Poly(ADP‐ribose) polymerase 1 (PARP1) and Ataxia telangectasia mutated (ATM) are two major sensors of SSBs and DSBs.”

In the paper

“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.”

In the paper

“DSB hotspots reside in long genes that are important for neuronal function and are risk factors for autism spectrum disorder and schizophrenia”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Wei et al, 2016, 2018
• Not checked yetcites Wang et al, 2020 source

In the paper

“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”

What the sources say

• Not checked yetcites Park et al, 2019 source

In the paper

“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.”

In the paper

“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.”

In the paper

“erroneous DSB repair could lead to mutations that result in transcriptomic dysfunction, which could further manifest at the cellular level as impaired synaptic signaling.”

In the paper

“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).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Lodato et al, 2015, 2018

In the paper

“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.”

In the paper

“SCAN1, caused by defective TDP1, is a similar neurodegenerative syndrome additionally characterized by peripheral neuropathy”

What the sources say

• Not checked yetcites Takashima et al, 2002 source
• Not checked yetcites El‐Khamisy et al, 2005

In the paper

“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).”

What the sources say

• Not checked yetcites Ghosh & Mitchell, 1999 source
• Not checked yetcites Moore et al, 2016 source
• Not checked yetcites Wang et al, 2018b

In the paper

“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.”

What the sources say

• Not checked yetcites Mullaart et al, 1990 source
• Not checked yetcites Adamec et al, 1999 source
• Not checked yetcites McKinnon, 2013 source

In the paper

“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).”

What the sources say

• Not checked yetcites Mertens et al, 2021 source

In the paper

“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).”

What the sources say

• Not checked yetcites Coppé et al, 2008 source
• Not checked yetcites Rodier et al, 2009 source
• Not checked yetcites Brzostek‐Racine et al, 2011

In the paper

“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).”

What the sources say

• Not checked yetcites Schaser et al, 2019 source

In the paper

“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).”

What the sources say

• Not checked yetcites Maiuri et al, 2017
• Not checked yetcites Gao et al, 2019

In the paper

“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).”

What the sources say

• Not checked yetcites d’Adda di Fagagna, 2008 source
• Not checked yetcites Miyamoto, 2011 source
• Not checked yetcites Li & Chen, 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Härtlova et al, 2015 source

In the paper

“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).”

In the paper

“This indicates that different phenotypes of DNA damage response deficits are mediated by different pathways, which may have preferential function in different cell types.”

In the paper

“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.”

What the sources say

• Not checked yetcites Miller et al, 2021 source

In the paper

“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).”

What the sources say

• Not checked yetcites Bussian et al, 2018 source
• Not checked yetcites Musi et al, 2018 source
• Not checked yetcites Zhang et al, 2019 source

In the paper

“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.”

What the sources say

• Not checked yetcites Bussian et al, 2018 source
• Not checked yetcites Musi et al, 2018 source

In the paper

“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).”

What the sources say

• Not checked yetcites Zhang et al, 2019 source

In the paper

“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).”

What the sources say

• Not checked yetcites Aditi et al, 2021

In the paper

“Importantly, as DNA damage is a well‐established source of inflammatory signaling, this uncovers a previously unstudied aspect of neuronal response to DNA damage.”

In the paper

“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).”

What the sources say

• Not checked yetcites Sharma et al, 2020 source
• Not checked yetcites Yu et al, 2020

In the paper

“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.”