Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke

Liu Yang; Lauren Guttman; Valina L Dawson; Ted M Dawson

doi:10.1016/j.bcp.2024.116174

Parthanatos: Mechanisms, modulation, and therapeutic prospects in neurodegenerative disease and stroke

Biochem Pharmacol. 2024 Mar 27:116174. doi: 10.1016/j.bcp.2024.116174. Online ahead of print.

Authors

Liu Yang¹, Lauren Guttman², Valina L Dawson³, Ted M Dawson⁴

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: vdawson1@jhmi.edu.
⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: tdawson@jhmi.edu.

PMID: 38552851
DOI: 10.1016/j.bcp.2024.116174

Abstract

Parthanatos is a cell death signaling pathway that has emerged as a compelling target for pharmaceutical intervention. It plays a pivotal role in the neuron loss and neuroinflammation that occurs in Parkinson's Disease (PD), Alzheimer's Disease (AD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS), and stroke. There are currently no treatments available to humans to prevent cell death in any of these diseases. This review provides an in-depth examination of the current understanding of the Parthanatos mechanism, with a particular focus on its implications in neuroinflammation and various diseases discussed herein. Furthermore, we thoroughly review potential intervention targets within the Parthanatos pathway. We dissect recent progress in inhibitory strategies, complimented by a detailed structural analysis of key Parthanatos executioners, PARP-1, AIF, and MIF, along with an assessment of their established inhibitors. We hope to introduce a new perspective on the feasibility of targeting components within the Parthanatos pathway, emphasizing its potential to bring about transformative outcomes in therapeutic interventions. By delineating therapeutic opportunities and known targets, we seek to emphasize the imperative of blocking Parthanatos as a precursor to developing disease-modifying treatments. This comprehensive exploration aims to catalyze a paradigm shift in our understanding of potential neurodegenerative disease therapeutics, advocating for the pursuit of effective interventions centered around Parthanatos inhibition.

Keywords: Apoptosis inducing factor (AIF); Cell Death; Macrophage migration inhibitory factor (MIF); PAANIB-1; Poly ADP-ribose (PAR); Poly ADP-ribose polymerase (PARP).

Publication types

Review

Abstract

Publication types

Grants and funding