Poly(ADP-ribose) Polymerase-1 in Amyloid Beta Toxicity and Alzheimer's Disease

Strosznajder, Joanna B.; Czapski, Grzegorz A.; Adamczyk, Agata; Strosznajder, Robert P.

doi:10.1007/s12035-012-8258-9

Cited by 93 publications

(62 citation statements)

References 69 publications

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“…Because studies suggest that PARP activation plays an important role in many pathophysiological states, including stroke, PD, and AD (3)(4)(5), it is likely that PARPdependent HK inhibition plays a role in the pathophysiology of these disorders. In support of this notion, redistribution and a decrease in HK activity has been shown to play a critical role in oxidative stress and neurodegeneration in AD (31).…”

Section: Discussionmentioning

confidence: 99%

“…P harmacological inhibition or genetic deletion of poly(ADPribose) polymerase-1 (PARP-1) is dramatically protective against a variety of toxic insults including ischemia reperfusion injury in the heart, brain, and other organs (1,2). PARP-1 activation also may play a role in several neurologic disorders such as Parkinson disease (PD), Alzheimer's disease (AD), autoimmune encephalomyelitis, and multiple sclerosis (3)(4)(5). PARP-1 activation plays a prominent role in necrotic cell death; the necrotic cell-death program initiated by PARP-1 activation has been designated "parthanatos" to distinguish it from other forms of cell death (6,7).…”

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confidence: 99%

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Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis

Andrabi¹,

Umanah²,

Chang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

279

273

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Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated "parthanatos" in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD + and energetic collapse, which have been thought to be caused by the consumption of cellular NAD + by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD + depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD + depletion in N-methyl-N-nitroso-N-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1-mediated mitochondrial dysfunction. Depleting neurons of NAD + with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis

Andrabi¹,

Umanah²,

Chang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

279

273

View full text Add to dashboard Cite

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“…Although ERC accumulation appears to be an age-associated phenomenon particular to yeast, recent data have shown increased rDNA content in the brains of patients suffering from of Alzheimer's disease or Lewy body dementia (43,44). Notably, PARP1 is activated in these diseases (45,46). Perhaps age-associated PARP1 activation and NAD + depletion could be caused by rDNA accumulation leading to loss of activity of NAD + -dependent enzymes, such as sirtuins, and consequent mitochondrial dysfunction.…”

Section: Stabilization Of G4 Structures Leads To Accelerated Agingmentioning

confidence: 99%

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Scheibye‐Knudsen

Tseng

Jensen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line converges on mitochondrial dysfunction caused by defects in ribosomal DNA transcription and activation of the DNA damage sensor poly-ADP ribose polymerase 1 (PARP1). Indeed, inhibition of ribosomal DNA transcription leads to mitochondrial dysfunction in a number of cell lines. Furthermore, machine-learning algorithms predict that diseases with defects in ribosomal DNA (rDNA) transcription have mitochondrial dysfunction, and, accordingly, this is found when factors involved in rDNA transcription are knocked down. Mechanistically, loss of CSA or CSB leads to polymerase stalling at non-B DNA in a neuroblastoma cell line, in particular at G-quadruplex structures, and recombinant CSB can melt G-quadruplex structures. Indeed, stabilization of G-quadruplex structures activates PARP1 and leads to accelerated aging in Caenorhabditis elegans. In conclusion, this work supports a role for impaired ribosomal DNA transcription in Cockayne syndrome and suggests that transcription-coupled resolution of secondary structures may be a mechanism to repress spurious activation of a DNA damage response.Cockayne syndrome | aging | polymerase I transcription | nucleolus | CSA | CSB

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“…66 Through yet ill-defined mechanisms, PARP1 hyperactivation may also contribute to the pathogenesis of Alzheimer's disease. 67,68 Finally, PARP activation downregulates mitochondrial respiration and oxidative metabolism, thereby enhancing age-related diseases (for example, diabetes and obesity). This effect could be ascribed to three different mechanisms, namely (i) direct PARylation of some metabolic enzymes potentially affecting their catalytic activity, (ii) effects on metabolism-relevant transcription factors and (iii) alteration of cellular NAD þ concentrations.…”

Section: Parp1 In Physiological and Pathological Responsesmentioning

confidence: 99%

Predictive biomarkers for cancer therapy with PARP inhibitors

Michels

Vitale²,

Saparbaev

et al. 2013

Oncogene

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Poly(ADP-ribose) polymerase (PARP) inhibitors have raised high expectations for the treatment of multiple malignancies. PARP inhibitors, which can be used as monotherapies or in combination with DNA-damaging agents, are particularly efficient against tumors with defects in DNA repair mechanisms, in particular the homologous recombination pathway, for instance due to BRCA mutations. Thus, deficient DNA repair provides a framework for the success of PARP inhibitors in medical oncology. Here, we review encouraging results obtained in recent clinical trials investigating the safety and efficacy of PARP inhibitors as anticancer agents. We discuss emerging mechanisms of regulation of homologous recombination and how inhibition of DNA repair might be used in cancer therapy. We surmise that the identification of patients that are likely to benefit from PARP inhibition will improve the clinical use of PARP inhibitors in a defined target population. Thus, we will place special emphasis on biomarker discovery.

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Poly(ADP-ribose) Polymerase-1 in Amyloid Beta Toxicity and Alzheimer's Disease

Cited by 93 publications

References 69 publications

Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis

Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis

Cockayne syndrome group A and B proteins converge on transcription-linked resolution of non-B DNA

Predictive biomarkers for cancer therapy with PARP inhibitors

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