2022
DOI: 10.15252/embr.202154217
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Mechanisms of DNA damage‐mediated neurotoxicity in neurodegenerative disease

Abstract: 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 … Show more

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Cited by 75 publications
(60 citation statements)
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“…Loss of genomic integrity is linked to aging and neurodegeneration (1,2). DNA damage repair pathways are transcriptionally prominent in the aging brain, and many age-associated neurodegenerative diseases exhibit both accumulation of DNA lesions and reduced DNA repair efficiency (3)(4)(5).…”
Section: Introductionmentioning
confidence: 99%
“…Loss of genomic integrity is linked to aging and neurodegeneration (1,2). DNA damage repair pathways are transcriptionally prominent in the aging brain, and many age-associated neurodegenerative diseases exhibit both accumulation of DNA lesions and reduced DNA repair efficiency (3)(4)(5).…”
Section: Introductionmentioning
confidence: 99%
“…This is likely due to an incomplete understanding of each disease's unique, as well as, shared pathophysiology. Markers of DNA damage are common among these disorders and defective DNA repair likely contributes to neurodegeneration 1 . The nuclear enzyme, poly‐ADP ribose (PAR) polymerase‐1 (PARP‐1), plays an important role in detecting and facilitating the repair of DNA damage 2 .…”
Section: Dna Damage: a Unifying Theme In Nervous System Disordersmentioning
confidence: 99%
“…This is likely due to the fact that all the PARP‐1 inhibitors approved to date for the treatment of cancer act by trapping PARP‐1 on DNA thereby inhibiting homologous DNA repair 16 . Impairment of DNA repair would not be desirable in disease of the nervous system 1 and would likely have liabilities in other chronic disorders characterized by cell death. Thus, inhibiting parthanatos without affecting PARP activity is greatly desired.…”
Section: Future Outlookmentioning
confidence: 99%
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“…Recent research has revealed a role of the SSBR system as a potential target for the regulation of cellular senescence and as a key player in a maintenance of neuronal integrity and plasticity [ 8 , 9 , 10 , 11 , 12 ]. Therefore, neural tissue is more sensitive to SSBR dysfunction, leading to various neurological disorders, such as age-associated and hereditary neurodegenerative diseases [ 4 , 5 , 13 , 14 ].…”
Section: Introductionmentioning
confidence: 99%