Emerging role of PARP-1 and PARthanatos in ischemic stroke

Abstract

Cell death is a key feature of neurological diseases, including stroke and neurodegenerative disorders. Studies in a variety of ischemic/hypoxic mouse models demonstrate that poly(ADP-ribose) polymerase 1 (PARP-1)-dependent cell death, also named PARthanatos, plays a pivotal role in ischemic neuronal cell death and disease progress. PARthanatos has its unique triggers, processors, and executors that convey a highly orchestrated and programmed signaling cascade. In addition to its role in gene transcription, DNA damage repair, and energy homeostasis through PARylation of its various targets, PARP-1 activation in neuron and glia attributes to brain damage following ischemia/reperfusion. Pharmacological inhibition or genetic deletion of PARP-1 reduces infarct volume, eliminates inflammation, and improves recovery of neurological functions in stroke. Here, we reviewed the role of PARP-1 and PARthanatos in stroke and their therapeutic potential.

Keywords: NAD+; PARP-1; PARthanatos; oxidative stress; stroke.

FIGURE 1

The functional domains of human PARP-1. Human PARP-1 contains a DNA-binding domain consisting of three zinc-binding motifs (Zn1, Zn2, and Zn3) and a nuclear localization signal (NLS) at its N-terminus, an auto-modification domain with BRCA1 C terminus (BRCT) motif in the center, and a catalytic domain with a WGR (tryptophan–glycine–arginine-rich) motif and a PARP signature motif at its C-terminus

FIGURE 2

PARthanatos signaling pathway following ischemia and reperfusion. Following ischemia and reperfusion injury, the excess release of glutamate activates NMDA receptor (NMDAR) and causes extracellular calcium influx, which leads to nitric oxide (NO) production and reactive oxygen species (ROS, e.g., superoxide, hydrogen peroxide, and peroxynitrite (ONOO−)) generation. Peroxynitrite can directly damage DNA and causes PAPR-1 hyperactivation. PARP-1 uses NAD⁺ as the substrate to generate poly-ADP-ribose (PAR) and catalyzes the addition of PAR to different accept proteins (AC) including PARP-1 itself, which might lead to energy depletion. Then, free PAR and/or PARylated accept proteins are translocated from nucleus to mitochondria and trigger AIF release from mitochondria. AIF recruits MIF to the nucleus where MIF functions as a nuclease and cuts DNA into a large fragmentation leading to chromatinolysis and subsequent cell death. TRPM2 receptor (TRPM2R) is regulated by free intracellular PAR and may amplify PARthanatos signaling by increasing calcium influx. In contrast, poly(ADP-ribose) glycohydrolase (PARG) dynamically cleaves PAR into mono ADP-ribose, which suppresses PAR death signal. In addition, Iduna is a PAR-dependent E3 ligase and interferes with PARthanatos by blocking PAR-AIF cross talk

FIGURE 3

Multifaceted effects of PARP-1 activation on neuron and microglia following ischemia/hypoxia. PARP-1 has multifaceted effects on neuron and glial cells and causes neuronal cell death following ischemic/hypoxic injury. First, PARP-1 hyperactivation leads to PAR accumulation, which enables nuclear-mitochondria cross talk and triggers AIF release and subsequent PARthanatos. Second, PARP-1 hyperactivation causes NAD⁺ depletion and regulates metabolic reprogramming, including inhibition of intracellular glucose uptake and hexokinase activity, ROS increase, and TCA cycle inhibition. Third, PARP-1 activation participates in regulation of ion homeostasis during oxidative stress by generation of PAR, which aggravates calcium influx through TRPM2 and AMPA receptors leading to a vicious cycle of more calcium influx and more excitotoxicity. Fourth, PARP-1 activation plays a role in microglial activation and neuroinflammation by activating transcription factors (such as NF-κB, p53, and AP-1) and their downstream gene expression