Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

Cardinale, Alessio; Racaniello, Mauro; Saladini, Serena; Chiara, Giovanna De; Mollinari, Cristiana; Stefano, Maria Chiara de; Pocchiari, Maurizio; Garaci, Enrico; Merlo, Daniela

doi:10.1074/jbc.m111.276550

Cited by 53 publications

(39 citation statements)

References 96 publications

(337 reference statements)

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“…Reports suggest that A␤ from the medium is internalized by the PC12 cells, enters their nuclei (57), and leads to death of PC12 cells (58). Studies also reveal that A␤ enters neurons and is present in their lysosomal system (59), whereas inhibition of its engulfment reduces death of neurons (60).…”

Section: Discussionmentioning

confidence: 99%

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

Saleem

Biswas

2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAmyloid-␤ (A␤)-induced neuron death is considered central to the pathogenesis of Alzheimer's disease (AD). Among several death modalities, autophagy and apoptosis play important roles in A␤-induced neuron death suggesting that there may be regulatory mechanisms that initiate both cell death pathways. However, molecules that govern both pathways have not been identified. Here, we report that, upon A␤ treatment, tribbles pseudokinase 3 (Trib3, an ortholog of Drosophila Tribbles) is up-regulated in neurons both in vivo and in vitro. Increased Trib3 levels inhibited the activity of the kinase Akt by interacting with it. As a result, forkhead box O1 (FoxO1), a transcription factor that is negatively regulated by Akt, was activated, translocated to the nucleus, and induced the pro-apoptotic gene BCL2-like 11 (Bim). Conversely, FoxO1 responded to A␤ insult by binding to the Trib3 gene promoter, enhancing its expression. Our investigations further revealed that Trib3 also induces autophagy. We found that Trib3 indirectly activates unc-51-like autophagy-activating kinase1 (Ulk1) by impeding phosphorylation of, and thus inactivating, a negative regulator of Ulk1, mechanistic target of rapamycin. Ulk1 activation augmented autophagosome formation and reduced autophagy flux. Thus, Trib3 was required for formation of autophagosomes, which accumulated in neurons as autophagic flux was thwarted. Most importantly, silencing endogenous Trib3 strongly protected neurons from A␤ insult. Our results suggest that a self-amplifying feed-forward loop among Trib3, Akt, and FoxO1 in A␤-treated neurons induces both apoptosis and autophagy, culminating in neuron death. Thus, Trib3 may serve as a potential therapeutic target for AD.

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Section: Discussionmentioning

confidence: 99%

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

Saleem

Biswas

2017

Journal of Biological Chemistry

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“…The neuropathological hallmarks of Alzheimer disease are the formation of amyloid plaques and neurofibrillary tangles. It may be significant, therefore, that the amyloid-β peptide can inhibit DNA-PK and thus hamper DNA repair through the NHEJ pathway 170 . In a similar vein, unphosphorylated tau, the major constituent of the neurofibrillary tangle, binds to the minor groove of the DNA double helix where its presence protects DNA from oxidative damage 171,172 .…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

Genomic integrity and the ageing brain

2015

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DNA damage is correlated with and may drive the ageing process. Neurons in the brain are postmitotic and are excluded from many forms of DNA repair; therefore, neurons are vulnerable to various neurodegenerative diseases. The challenges facing the field are to understand how and when neuronal DNA damage accumulates, how this loss of genomic integrity might serve as a 'time keeper' of nerve cell ageing and why this process manifests itself as different diseases in different individuals.

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“…Aurintricarboxylic acid, a nuclease inhibitor, was shown to prevent apoptotic DNA fragmentation and delays cell death caused by Aβ [187]. Sub-lethal doses of Aβ contribute to loss of DNA-PK activity, thereby, leading to delayed DNA repair [188]. Furthermore, J20 mice expressing high level of hAPP showed the presence of DSB marker γH2AX in brain, suggesting a possible link between Aβ accumulation and increased DSBs formation [21].…”

Section: Dna Repair Defects and Neuronal Phenotypesmentioning

confidence: 99%

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

Weng

Dharmalingam

Vasquez

et al. 2017

Mechanisms of Ageing and Development

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A foremost challenge for the neurons, which are among the most oxygenated cells, is the genome damage caused by chronic exposure to endogenous reactive oxygen species (ROS), formed as cellular respiratory byproducts. Strong metabolic activity associated with high transcriptional levels in these long lived post-mitotic cells render them vulnerable to oxidative genome damage, including DNA strand breaks and mutagenic base lesions. There is growing evidence for the accumulation of unrepaired DNA lesions in the central nervous system (CNS) during accelerated ageing and progressive neurodegeneration. Several germ line mutations in DNA repair or DNA damage response (DDR) signaling genes are uniquely manifested in the phenotype of neuronal dysfunction and are etiologically linked to many neurodegenerative disorders. Studies in our lab and elsewhere revealed that pro-oxidant metals, ROS and misfolded amyloidogenic proteins not only contribute to genome damage in CNS, but also impede their repair/DDR signaling leading to persistent damage accumulation, a common feature in sporadic neurodegeneration. Here, we have reviewed recent advances in our understanding of the etiological implications of DNA damage vs. repair imbalance, abnormal DDR signaling in triggering neurodegeneration and potential of DDR as a target for the amelioration of neurodegenerative diseases.

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Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

Cited by 53 publications

References 96 publications

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

Genomic integrity and the ageing brain

Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target?

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