PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells
Masato Mashimo, Xiangning Bu, Kazumasa Aoyama, Jiro Kato, Hiroko Ishiwata-Endo, Linda A. Stevens, Atsushi Kasamatsu, Lynne A. Wolfe, Camilo Toro, David Adams, Thomas Markello, William A. Gahl, Joel Moss
Masato Mashimo, Xiangning Bu, Kazumasa Aoyama, Jiro Kato, Hiroko Ishiwata-Endo, Linda A. Stevens, Atsushi Kasamatsu, Lynne A. Wolfe, Camilo Toro, David Adams, Thomas Markello, William A. Gahl, Joel Moss
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Research Article Genetics Therapeutics

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.

Authors

Masato Mashimo, Xiangning Bu, Kazumasa Aoyama, Jiro Kato, Hiroko Ishiwata-Endo, Linda A. Stevens, Atsushi Kasamatsu, Lynne A. Wolfe, Camilo Toro, David Adams, Thomas Markello, William A. Gahl, Joel Moss

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Figure 5

Exacerbated cerebral ischemic injury and enhanced PAR and AIF accumulation in ARH3–/– mice are prevented by PARP inhibition.

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Exacerbated cerebral ischemic injury and enhanced PAR and AIF accumulati...
(A) Quantification of infarct volume Data are mean ± SEM of values from WT (n = 5) and ARH3–/– (n = 5) mice. *P < 0. 05, **P < 0.01. (B) Percentage of PAR-labeled of cortical neurons in ischemic cortex. Data are mean ± SEM of values obtained from 1264 and 1783 cortical neurons in control- and veliparib-treated WT mice (n = 5), respectively; and 1453 and 1793 cortical neurons in control- and veliparib-treated ARH3–/– mice (n = 5), respectively. ***P < 0.001. (C) Nuclear localization of AIF. Data are mean ± SEM of values obtained from 349 and 211 cortical neurons in control- and veliparib-treated WT mice (n = 5), respectively; and 394 and 717 cortical neurons in control- and veliparib-treated ARH3–/– mice (n = 5), respectively. ***P < 0.001. (D) Percentage of neurons with DNA fragmentation detected by TUNEL assay and AIF translocation to nuclei. Data are mean ± SEM of values obtained 802 and 847 cortical neurons in control and veliparib-treated WT mice (n = 5), respectively; and 646 and 714 cortical neurons in control and veliparib-treated ARH3–/– mice (n = 5), respectively. ***P < 0.001. Two-way ANOVA with Bonferroni’s post-hoc test used in all panels.