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
The human brain constitutes only 2–3% of the total body weight but monopolizes about 15% of the total blood flow, and it consumes about 20% of the total oxygen inhaled by the lungs
Ligand binding domains of human estrogen receptor-related receptors (ERRs) were fused with the Gal4 DNA binding domain, and each of the resulting Gal4-ERR fusion proteins was expressed in HEK293A cells, together with a luciferase reporter plasmid, which contains 4 copies of GalRE (Kamei et al, 2003; Yamamoto et al, 2001), a Gal4-responsive element in the promoter region
These results indicated that esculetin is able to function as an ERR agonist for all three ERRs
Summary
The human brain constitutes only 2–3% of the total body weight but monopolizes about 15% of the total blood flow, and it consumes about 20% of the total oxygen inhaled by the lungs. The brain needs a lot of energy, namely ATP, for its functions and survival. A decrease in ATP production in certain area(s) of the brain or the central nervous system can lead to neuronal cell death in the affected area(s) and cause ischemic or degenerative neuronal diseases. Parkinson's disease is caused by gradual cell death of dopaminergic neurons in the substantia nigra, and therapeutic chemicals or drugs that prevent this cell death are currently not available. In the early 1980s, certain numbers of drug users near San Francisco were observed manifesting Parkinson's disease phenotypes (Langston et al, 1983). The examination clarified that they suffered from accidental intoxication by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which was a contaminant in the drug they used. It was found that 1-methyl4-phenylpyridinium (MPP +), a metabolite of MPTP, but not MPTP
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