Targeting mitophagy in Parkinson's disease

J Biol Chem. Jan-Jun 2021;296:100209. doi: 10.1074/jbc.REV120.014294. Epub 2020 Dec 24.

Abstract

The genetics and pathophysiology of Parkinson's disease (PD) strongly implicate mitochondria in disease aetiology. Elegant studies over the last two decades have elucidated complex molecular signaling governing the identification and removal of dysfunctional mitochondria from the cell, a process of mitochondrial quality control known as mitophagy. Mitochondrial deficits and specifically reduced mitophagy are evident in both sporadic and familial PD. Mendelian genetics attributes loss-of-function mutations in key mitophagy regulators PINK1 and Parkin to early-onset PD. Pharmacologically enhancing mitophagy and accelerating the removal of damaged mitochondria are of interest for developing a disease-modifying PD therapeutic. However, despite significant understanding of both PINK1-Parkin-dependent and -independent mitochondrial quality control pathways, the therapeutic potential of targeting mitophagy remains to be fully explored. Here, we provide a summary of the genetic evidence supporting the role for mitophagy failure as a pathogenic mechanism in PD. We assess the tractability of mitophagy pathways and prospects for drug discovery and consider intervention points for mitophagy enhancement. We explore the numerous hit molecules beginning to emerge from high-content/high-throughput screening as well as the biochemical and phenotypic assays that enabled these screens. The chemical and biological properties of these reference compounds suggest many could be used to interrogate and perturb mitochondrial biology to validate promising drug targets. Finally, we address key considerations and challenges in achieving preclinical proof-of-concept, including in vivo mitophagy reporter methodologies and disease models, as well as patient stratification and biomarker development for mitochondrial forms of the disease.

Keywords: PINK1; Parkin; Parkinson’s disease; biomarker; drug discovery; mitochondria; mitophagy.

Publication types

  • Review

MeSH terms

  • Antiparkinson Agents / pharmacology
  • Drug Discovery
  • Humans
  • Mitochondria / metabolism
  • Mitophagy* / drug effects
  • Mutation
  • Parkinson Disease / genetics
  • Parkinson Disease / pathology*
  • Protein Kinases / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Antiparkinson Agents
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase