Kinases control of regulated cell death revealing druggable targets for Parkinson's disease.

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity in the striatum, and dopaminergic neuronal death in the substantia nigra pars compacta. Cell death has a significant effect on the development and progression of PD. Extensive research over the last few decades has unveiled new regulated cell death (RCD) mechanisms that are not dependent on apoptosis such as necroptosis, ferroptosis, and others. In this review, we will overview the mechanistic pathways of different types of RCD. Unlike accidental cell death, RCD subroutines can be regulated and the RCD-associated kinases are potential druggable targets. Hence, we will address an overview and analysis of different kinases regulating apoptosis such as receptor-interacting protein kinase 1 (RIPK-1), RIPK3, mixed lineage kinase (MLK), Ataxia telangiectasia muted (ATM), cyclin-dependent kinase (CDK), death-associated protein kinase 1 (DAPK1), Apoptosis-signaling kinase-1 (ASK-1), and Leucine-rich repeat kinase-2 (LRRK2). In addition to the role of RIPK1, RIPK3, and Mixed Lineage Kinase Domain like Pseudokinase (MLKL) in necroptosis. We also overview functions of AMP-kinase (AMPK), protein kinase C (PKC), RIPK3, and ATM in ferroptosis. We will recap the anti-apoptotic, anti-necroptotic, and anti-ferroptotic effects of different kinase inhibitors in different models of PD. Finally, we will discuss future challenges in the repositioning of kinase inhibitors in PD. In conclusion, this review kicks-start targeting RCD from a kinases perspective, opening novel therapeutic disease-modifying therapeutic avenues for PD.