Oxidative Stress and Disturbed Glutamate Transport in Hereditary Nucleotide Repair Disorders

Hayashi, Masaharu; Itoh, Masahiro; Araki, Satoshi; Kumada, Satoko; Shioda, Kei; Tamagawa, Kimiko; Mizutani, Toshio; Morimatsu, Yoshio; Minagawa, M; Oda, Masaya

doi:10.1093/jnen/60.4.350

Cited by 49 publications

(30 citation statements)

References 26 publications

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“…Not necessarily. Examination of CS brain tissue has observed evidence of neuroinflammation, including activated microglia [49], markers of oxidative stress and lipid peroxidation products [76]. Since myelin is primarily composed of lipid, oxidative stress from an inflammatory response in white matter would be expected to generate lipid peroxidation products.…”

Section: Dysmyelination and Brain Calcification In Ags And Cs Neurolomentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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The classic model for neurodegeneration due to mutations in DNA repair genes holds that DNA damage accumulates in the absence of repair, resulting in the death of neurons. This model was originally put forth to explain the dramatic loss of neurons observed in patients with xeroderma pigmentosum neurologic disease, and is likely to be valid for other neurode-generative diseases due to mutations in DNA repair genes. However, in trichiothiodystrophy (TTD), Aicardi-Goutières syndrome (AGS), and Cockayne syndrome (CS), abnormal myelin is the most prominent neuropathological feature. Myelin is synthesized by specific types of glial cells called oligodendrocytes. In this review, we focus on new studies that illustrate two disease mechanisms for myelin defects resulting from mutations in DNA repair genes, both of which are fundamentally different than the classic model described above. First, studies using the TTD mouse model indicate that TFIIH acts as a co-activator for thyroid hormone-dependent gene expression in the brain, and that a causative XPD mutation in TTD results in reduction of this co-activator function and a dysregulation of myelin-related gene expression. Second, in AGS, which is caused by mutations in either TREX1 or RNASEH2, recent evidence indicates that failure to degrade nucleic acids produced during S-phase triggers activation of the innate immune system, resulting in myelin defects and calcification of the brain. Strikingly, both myelin defects and brain calcification are both prominent features of CS neurologic disease. The similar neuropathology in CS and AGS seems unlikely to be due to the loss of a common DNA repair function, and based on the evidence in the literature, we propose that vascular abnormalities may be part of the mechanism that is common to both diseases. In summary, while the classic DNA damage accumulation model is applicable to the neuronal death due to defective DNA repair, the myelination defects and brain calcification seem to be better explained by quite different mechanisms. We discuss the implications of these different disease mechanisms for the rational development of treatments and therapies.

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Section: Dysmyelination and Brain Calcification In Ags And Cs Neurolomentioning

confidence: 99%

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

2008

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“…60,64,[67][68][69] Cockayne syndrome cells respond poorly to oxidative stress. 70 Whether mitochondrial dysfunction plays a role in hearing loss, retinitis pigmentosa, and other manifestations of Cockayne syndrome remains to be determined. Mitochondrial function seems not to have been studied thus far in Cockayne syndrome; it was normal in the muscle of case 6.…”

Section: Pathophysiologymentioning

confidence: 99%

Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

et al. 2006

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Cockayne syndrome and xeroderma pigmentosum-Cockayne syndrome complex are rare autosomal recessive disorders with poorly understood biology. They are characterized by profound postnatal brain and somatic growth failure and by degeneration of multiple tissues resulting in cachexia, dementia, and premature aging. They result in premature death, usually in childhood, exceptionally in adults. This study compares the clinical course and pathology of a man with Cockayne syndrome group A who died at age 31½ years with 15 adequately documented other adults with Cockayne syndrome and 5 with xeroderma pigmentosum-Cockayne syndrome complex. Slowing of head and somatic growth was apparent before age 2 years, mental retardation and slowly progressive spasticity at 4 years, ataxia and hearing loss at 9 years, visual impairment at 14 years, typical Cockayne facies at 17 years, and cachexia and dementia in his twenties, with a retained outgoing personality. He experienced several transient right and left hemipareses and two episodes of status epilepticus following falls. Neuropathology disclosed profound microencephaly, bilateral old subdural hematomas, white-matter atrophy, tigroid leukodystrophy with string vessels, oligodendrocyte proliferation, bizarre reactive astrocytes, multifocal dystrophic calcification that was most marked in the basal ganglia, advanced atherosclerosis, mixed demyelinating and axonal neuropathy, and neurogenic muscular atrophy. Cellular degeneration of the organ of Corti, spiral and vestibular ganglia, and all chambers of the eye was severe. Rarely, and for unexplained reasons, in some patients with Cockayne syndrome the course is slower than usual, resulting in survival into adulthood. The profound dwarfing, failure of brain growth, cachexia, selectivity of tissue degeneration, and poor correlation between genotypes and phenotypes are not understood. Deficient repair of DNA can increase vulnerability to oxidative stress and play a role in the premature aging, but why patients with mutations in xeroderma pigmentosum genes present with the Cockayne syndrome phenotype is still not known.

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“…High levels of oxidative metabolism occur in the brain and are increased in many instances of neurodegeneration (Kruman, 2004). Endogenous oxidative damage has been reported in the brains of repair deficient patients, although more prominently in XPA than CS patients (Hayashi et al, 2005;Hayashi et al, 2001). The granule and Purkinje cells of the cerebellum appear to be targets for many cellular toxins (Fonnum and Lock, 2000;Fonnum and Lock, 2004) and the Purkinje cells have unique deficits of several enzymes that present a low threshold for cell death from intrinsic or extrinsic sources (Welsh et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair

et al. 2007

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Cockayne syndrome (CS) is a progressive childhood neurodegenerative disorder associated with a DNA repair defect caused by mutations in either of two genes, CSA and CSB. These genes are involved in nucleotide excision repair (NER) of DNA damage from ultraviolet (UV) light, other bulky chemical adducts and reactive oxygen in transcriptionally active genes (transcription coupled repair, TCR). For a long period it has been assumed that the symptoms of CS patients are all due to reduced TCR of endogenous DNA damage in the brain, together with unexplained unique sensitivity of specific neural cells in the cerebellum. Not all the symptoms of CS patients are however easily related to repair deficiencies, so we hypothesize that there are additional pathways relevant to the disease, particularly those that are downstream consequences of a common defect in the E3 ubiquitin ligase associated with the CSA and CSB gene products. We have found that the CSB defect results in altered expression of anti-angiogenic and cell cycle genes and proteins at the level of both gene expression and protein lifetime. We find an over-abundance of p21 due to reduced protein turnover, possibly due to the loss of activity of the CSA/CSB E3 ubiquitylation pathway. Increased levels of p21 can result in growth inhibition, reduced repair from the p21-PCNA interaction, and increased generation of reactive oxygen. Consistent with increased reactive ozygen levels we find that CS-A and -B cells grown under ambient oxygen show increased DNA breakage, as compared to xeroderma pigmentosum cells. Thus the complex symptoms of CS may be due to multiple, independent downstream targets of the E3 ubiquitylation system that results in increased DNA damage, reduced transcription coupled repair, and inhibition of cell cycle progression and growth.

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Oxidative Stress and Disturbed Glutamate Transport in Hereditary Nucleotide Repair Disorders

Cited by 49 publications

References 26 publications

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Do all of the neurologic diseases in patients with DNA repair gene mutations result from the accumulation of DNA damage?

Cockayne Syndrome in Adults: Review With Clinical and Pathologic Study of a New Case

Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair

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