DNA strand breaks in Alzheimer's disease

Adamec, Emil; Vonsattel, Jean Paul; Nixon, Ralph A.

doi:10.1016/s0006-8993(99)02004-1

Cited by 154 publications

(95 citation statements)

References 57 publications

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“…Elevated DSB levels have been noted in mouse models of Alzheimer disease (20 -22), and a reduction in levels of DSB repair proteins has been described in Alzheimer disease patients compared with age-matched controls (35)(36)(37)(38). Expression of polyQ43 can activate ATM and phosphorylate H2AX in PC12 cells (39), and phosphorylated H2AX associated with DSBs has also been reported in neuronal cultures expressing mutant polyQ (40).…”

Section: Discussionmentioning

confidence: 99%

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

Lü

Boschetti

Tunnacliffe

2015

Journal of Biological Chemistry

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Background:The formation of juxtanuclear aggresomes from aggregation-prone proteins is widely believed to be protective to cells. Results: Cell lines containing aggresomes suffer from DNA double-strand breaks, cell cycle arrest, mitotic defects, and apoptosis. Conclusion: Long term accumulation of aggresomes has detrimental effects on nuclear function in cells. Significance: This study provides the first evidence that aggresomes can cause significant cellular dysfunction in dividing cells.

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Section: Discussionmentioning

confidence: 99%

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

Lü

Boschetti

Tunnacliffe

2015

Journal of Biological Chemistry

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“…Compromised DNA repair mechanisms could therefore render neurons vulnerable to glutamate receptor-mediated dysfunction and death. Indeed, patients with genetic defects in DNA repair often exhibit major neurodegenerative phenotypes (63) and DNA damage occurs in neurodegenerative disorders such as Alzheimer disease in which overactivation of glutamate receptors is implicated (15,27,62,64). A better understanding of the signaling pathways that enhance DNA repair may therefore lead to novel approaches for protecting neurons against injury and neurodegenerative disorders.…”

Section: Discussionmentioning

confidence: 99%

Neurons Efficiently Repair Glutamate-induced Oxidative DNA Damage by a Process Involving CREB-mediated Up-regulation of Apurinic Endonuclease 1

Yang

Tadokoro

Keijzers

et al. 2010

Journal of Biological Chemistry

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Glutamate, the major excitatory neurotransmitter in the brain, activates receptors coupled to membrane depolarization and Ca 2؉ influx that mediates functional responses of neurons including processes such as learning and memory. Here we show that reversible nuclear oxidative DNA damage occurs in cerebral cortical neurons in response to transient glutamate receptor activation using non-toxic physiological levels of glutamate. This DNA damage was prevented by intracellular Ca 2؉ chelation, the mitochondrial superoxide dismutase mimetic MnTMPyP (Mn-5,10,15,20-tetra(4-pyridyl)-21H,23H-porphine chloride tetrakis(methochloride)), and blockade of the permeability transition pore. The repair of glutamate-induced DNA damage was associated with increased DNA repair activity and increased mRNA and protein levels of apurinic endonuclease 1 (APE1 which mediate long lasting changes in neuronal structure and function (2-5). Glutamate receptor activation also stimulates an increase in mitochondrial respiration (electron transport) to generate the ATP necessary to drive the activity of ion-motive ATPases that restore ion gradients across cellular membranes (6). Mitochondrial Ca 2ϩ uptake and increased mitochondrial respiration can result in production of the damaging free radical superoxide (7, 8), as well as mitochondrial membrane permeability changes that trigger cell death, a process called excitotoxicity (9, 10).Damage to DNA in neurons occurs early during excitotoxicity (11, 12) and may be a pivotal event in cell death because selective inhibition or knockdown of the DNA damage response proteins p53 (13, 14) and PARP-1 (15, 16) can prevent glutamate-induced neuronal death. Ca 2ϩ and mitochondriaderived superoxide are believed to play key roles in glutamateinduced DNA damage and cell death because PARP-1 activation is mediated by Ca 2ϩ and mitochondrial reactive oxygen species (17), and because mitochondrial Mn-SOD and exogenous antioxidants protect neurons against excitotoxicity (18 -20). However, it is not known if oxidative lesions to nuclear DNA occur in response to non-pathological subtoxic levels of glutamate receptor activation, nor is it known if and how neurons might respond to such glutamate-induced DNA damage.Base excision repair (BER) is the primary DNA repair pathway for removal of small base modifications such as alkylation, deamination, and oxidation (21,22). This process occurs both in the nucleus and in mitochondria. By far most information on the molecular mechanisms of DNA damage and repair comes from studies of non-neuronal cells, and the extent of DNA damage and repair in neurons under physiological and pathological conditions is largely unknown (23

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“…These cell types have their origin in neural stem cells (NSC), multipotent, predifferentiated stem cells that will develop into neuronal and glial lineages, but that FIG. 4. Epigenetic mechanisms in the development of the nervous system.…”

Section: A Development Of the Nervous System And Cellular Differentimentioning

confidence: 99%

“…During the processing of APP, an intracellular fragment is released into the cytosol, which was shown in vitro to interact with the HAT TIP60 through the protein Fe65, and the resulting complex was suggested to enhance gene transcription (40). This complex may also play a role in histone H4 acetylation required for DNA repair, an interesting notion considering that the amount of DNA doublestrand breaks are increased in AD and AD models (4,159). Furthermore, PS1 was shown to play an inhibitory role on the HAT CBP through proteasomal degradation, and mutations in PS1 found in hereditary AD were shown to result in aberrantly high CBP activity (216).…”

Section: B Alzheimer's Diseasementioning

confidence: 99%

Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes

Gräff

Kim

Dobbin

et al. 2011

Physiological Reviews

318

246

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Over the past decade, it has become increasingly obvious that epigenetic mechanisms are an integral part of a multitude of brain functions that range from the development of the nervous system over basic neuronal functions to higher order cognitive processes. At the same time, a substantial body of evidence has surfaced indicating that several neurodevelopmental, neurodegenerative, and neuropsychiatric disorders are in part caused by aberrant epigenetic modifications. Because of their inherent plasticity, such pathological epigenetic modifications are readily amenable to pharmacological interventions and have thus raised justified hopes that the epigenetic machinery provides a powerful new platform for therapeutic approaches against these diseases. In this review, we give a detailed overview of the implication of epigenetic mechanisms in both physiological and pathological brain processes and summarize the state-of-the-art of “epigenetic medicine” where applicable. Despite, or because of, these new and exciting findings, it is becoming apparent that the epigenetic machinery in the brain is highly complex and intertwined, which underscores the need for more refined studies to disentangle brain-region and cell-type specific epigenetic codes in a given environmental condition. Clearly, the brain contains an epigenetic “hotspot” with a unique potential to not only better understand its most complex functions, but also to treat its most vicious diseases.

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DNA strand breaks in Alzheimer's disease

Cited by 154 publications

References 57 publications

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

Long Term Aggresome Accumulation Leads to DNA Damage, p53-dependent Cell Cycle Arrest, and Steric Interference in Mitosis

Neurons Efficiently Repair Glutamate-induced Oxidative DNA Damage by a Process Involving CREB-mediated Up-regulation of Apurinic Endonuclease 1

Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes

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