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

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.

Highlights

• •

  We describe two types of ATP regulators: one limits ATP consumption, while the other enhances ATP production.

• •

  ATP regulators maintain ATP levels and protect neuronal cells from ER stress and eventual cell death.

• •

  ATP regulators mitigate disease phenotypes in mouse models of Parkinson's disease.

ATP is essential in human activities and health. We hypothesize that maintaining ATP levels may help to preserve vulnerable brain cells in neurodegenerative diseases like Parkinson's disease (PD). For this purpose, we developed and tested two types of chemical compounds, one for limiting ATP consumption and the other for enhancing ATP production. These chemicals, which we call “ATP regulators”, indeed mitigated the pathological phenotypes in two mouse models of PD, indicating that ATP regulation is a promising therapeutic strategy for currently incurable diseases, such as PD, and possibly other neurodegenerative diseases.