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Role of Poly(ADP-ribose) Polymerase in Brain Inflammation and Neuroinjury

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Handbook of Neurochemistry and Molecular Neurobiology

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Abstract:

Poly(ADP-ribose) polymerase-1 (PARP-1) is a DNA-binding protein, which is primarily activated by nicks in the DNA molecule. It regulates the activity of various enzymes, including itself, and those involved in the control of DNA metabolism. Upon binding to DNA breaks, activated PARP cleaves NAD + into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins including histones, transcription factors, and PARP itself. Poly(ADP-ribosylation) contributes to DNA repair and to the maintenance of genomic stability. Evidence obtained with pharmacological PARP inhibitors of various structural classes, as well as animals lacking the PARP-1 enzyme indicate that PARP plays an important role in cerebral ischemia/reperfusion, stroke, neurotrauma, neuroinjury, and neurodegeneration. Overactivation of PARP consumes NAD + and ATP culminating in cell dysfunction and necrosis. PARP activation can also act as a signal that initiates cell death programs, for instance through apoptosis-inducing factor (AIF) translocation. PARP has also been shown to associate with and regulate the function of several transcription factors. Of special interest is the enhancement by PARP of nuclear factor (NF)-κB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators. Via this mechanism, PARP is involved in the upregulation of numerous proinflammatory genes that play a pathogenetic role in the later stage of central nervous system (CNS) diseases. Here, we review the roles of PARP in DNA damage signaling and cell death and summarize the pathogenetic role of PARP in neuroinflammation and neuroinjury.

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Abbreviations

AIF:

apoptosis-inducing factor

APP:

amyloid precursor protein

CNS:

central nervous system

EAE:

experimental allergic encephalomyelitis

ICAM-1:

intercellular adhesion molecule-1

IFN:

interferon

IL:

interleukin

iNOS:

inducible nitric oxide synthase

MCAO:

middle cerebral artery occlusion

MS:

multiple sclerosis

NOS:

nitric oxide synthase

PARG:

poly(ADP-ribose) glycohydrolase

PARP:

poly(ADP-ribose) polymerase

PARP −/− cells/mice:

cells/mice homozygous for disrupted poly(ADP-ribose) polymerase genes

ROS:

reactive oxygen species

SCI:

spinal cord injury

TBI:

traumatic brain injury

TNF-α:

tumor necrosis factor-α

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Acknowledgments

The work in the authors’ laboratories is supported by grants from the National Institutes of Health and the Hungarian Ministry of Health.

Authors
  1. G. S. Scott
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  2. K. Komjáti
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  3. V. C. Besson
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  4. C. Szabó
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Editor information

Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, 10962, New York, Orangeburg, USA

    Abel Lajtha (Director) (Director)

  2. The Buniatian Institute of Biochemistry the National Academy of Sciences, 5/1 Sevag str., 375014, Yerevan, Republic of Armenia

    Armen Galoyan

  3. Dept. Immunophysiology Medical Faculty, Inst. of Normal and Pathological Physiology, Deutschhausstrase 2, D–35037, Marburg, Germany

    Hugo O. Besedovsky

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© 2008 Springer Science+Business Media, LLC

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Scott, G.S., Komjáti, K., Besson, V.C., Szabó, C. (2008). Role of Poly(ADP-ribose) Polymerase in Brain Inflammation and Neuroinjury. In: Lajtha, A., Galoyan, A., Besedovsky, H.O. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30398-7_20

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