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 3

Hippocampal neurons from proband’s deceased sister show an increase in nuclear PAR and AIF-mediated DNA fragmentation.

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Hippocampal neurons from proband’s deceased sister show an increase in n...
(A) PAR accumulation in nuclei of hippocampal neurons in the proband’s deceased sister, with homozygous mutation of ARH3. Hippocampal sections were subjected to immunolabeling with anti-PAR (green) and anti-NeuN (red) antibodies. Nuclei were stained with DAPI (blue). CA1, cornu ammonis 1; DG, dentate gyrus. Scale bar: 20 μm. (B) Percentage of PAR-labeled nuclei of neurons in CA1 and DG. Data are mean ± SEM of values obtained from 980 and 426 neurons in CA1 and DG, respectively. (C) AIF translocation to nuclei and DNA fragmentation in hippocampal neurons of the proband’s sister. Brain sections were subjected to TUNEL assay (right blue) and immunolabeling with anti-AIF (green) and NeuN (red) antibodies. Nuclei were stained with DAPI (blue). Scale bar: 20 μm. (D) Percentage of neurons with DNA fragmentation detected by TUNEL assay and AIF translocation to nuclei. Data are mean ± SEM of values obtained 1571 and 1308 neurons in CA1 and DG, respectively.