ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease

EBioMedicine. 2017 Aug;22:225-241. doi: 10.1016/j.ebiom.2017.07.024. Epub 2017 Jul 25.

Abstract

Parkinson's disease is assumed to be caused by mitochondrial dysfunction in the affected dopaminergic neurons in the brain. We have recently created small chemicals, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption. By contrast, agonistic ligands of ERRs (estrogen receptor-related receptors) are expected to raise cellular ATP levels via enhancing ATP production. Here, we show that esculetin functions as an ERR agonist, and its addition to culture media enhances glycolysis and mitochondrial respiration, leading to elevated cellular ATP levels. Subsequently, we show the neuroprotective efficacies of KUSs, esculetin, and GSK4716 (an ERRγ agonist) against cell death in Parkinson's disease models. In the surviving neurons, ATP levels and expression levels of α-synuclein and CHOP (an ER stress-mediated cell death executor) were all rectified. We propose that maintenance of ATP levels, by inhibiting ATP consumption or enhancing ATP production, or both, would be a promising therapeutic strategy for Parkinson's disease.

Keywords: ATP; Dopaminergic neurons; ER stress; Mitochondria; Parkinson's disease; α-Synuclein.

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Animals
  • Cell Death / drug effects
  • Culture Media
  • Disease Models, Animal
  • Estrogens / administration & dosage*
  • Estrogens / pharmacology
  • Glycolysis
  • Glycosides / administration & dosage
  • Glycosides / pharmacology
  • HEK293 Cells
  • Humans
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • PC12 Cells
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Pregnenolone / administration & dosage
  • Pregnenolone / analogs & derivatives
  • Pregnenolone / pharmacology
  • Rats
  • Small Molecule Libraries / administration & dosage*
  • Small Molecule Libraries / pharmacology

Substances

  • Culture Media
  • Estrogens
  • Glycosides
  • Small Molecule Libraries
  • esculentin steroid
  • Pregnenolone
  • Adenosine Triphosphate