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PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells.

ABSTRACT: Poly(ADP-ribosyl)ation refers to the covalent attachment of ADP-ribose to protein, generating branched, long chains of ADP-ribose moieties, known as poly(ADP-ribose) (PAR). Poly(ADP-ribose) polymerase 1 (PARP1) is the main polymerase and acceptor of PAR in response to DNA damage. Excessive intracellular PAR accumulation due to PARP1 activation leads cell death in a pathway known as parthanatos. PAR degradation is mainly controlled by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose-acceptor hydrolase 3 (ARH3). Our previous results demonstrated that ARH3 confers protection against hydrogen peroxide (H2O2) exposure, by lowering cytosolic and nuclear PAR levels and preventing apoptosis-inducing factor (AIF) nuclear translocation. We identified a family with an ARH3 gene mutation that resulted in a truncated, inactive protein. The 8-year-old proband exhibited a progressive neurodegeneration phenotype. In addition, parthanatos was observed in neurons of the patient's deceased sibling, and an older sibling exhibited a mild behavioral phenotype. Consistent with the previous findings, the patient's fibroblasts and ARH3-deficient mice were more sensitive, respectively, to H2O2 stress and cerebral ischemia/reperfusion-induced PAR accumulation and cell death. Further, PARP1 inhibition alleviated cell death and injury resulting from oxidative stress and ischemia/reperfusion. PARP1 inhibitors may attenuate the progression of neurodegeneration in affected patients with ARH3 deficiency.

SUBMITTER: Mashimo M

PROVIDER: S-EPMC6478412 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells.

Mashimo Masato M Bu Xiangning X Aoyama Kazumasa K Kato Jiro J Ishiwata-Endo Hiroko H Stevens Linda A LA Kasamatsu Atsushi A Wolfe Lynne A LA Toro Camilo C Adams David D Markello Thomas T Gahl William A WA Moss Joel J

JCI insight 20190221 4

Poly(ADP-ribosyl)ation refers to the covalent attachment of ADP-ribose to protein, generating branched, long chains of ADP-ribose moieties, known as poly(ADP-ribose) (PAR). Poly(ADP-ribose) polymerase 1 (PARP1) is the main polymerase and acceptor of PAR in response to DNA damage. Excessive intracellular PAR accumulation due to PARP1 activation leads cell death in a pathway known as parthanatos. PAR degradation is mainly controlled by poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose-acceptor ...[more]

PMID: 30830864

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PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells.

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PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells.

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