2. Academic Validation
  3. PARP1 inhibition alleviates injury in ARH3-deficient mice and human cells

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

  • JCI Insight. 2019 Feb 21;4(4):e124519. doi: 10.1172/jci.insight.124519.
Masato Mashimo 1,  Xiangning Bu 1,  Kazumasa Aoyama 1,  Jiro Kato 1,  Hiroko Ishiwata-Endo 1,  Linda A Stevens 1,  Atsushi Kasamatsu 1,  Lynne A Wolfe 2,  Camilo Toro 2,  David Adams 2 3,  Thomas Markello 2,  William A Gahl 2 3,  Joel Moss 1
Affiliations

Affiliations

  • 1 Pulmonary Branch, National Heart, Lung, and Blood Institute (NHLBI).
  • 2 NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, and.
  • 3 Office of the Clinical Director, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
PMID: 30830864 DOI: 10.1172/jci.insight.124519
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.

Keywords

Genetic diseases; Genetics; Neurodegeneration; Therapeutics.

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