title: Ursocholanic acid rescues mitochondrial function in common forms of familial Parkinson's disease.
abstract: Previous drug screens aiming to identify disease-modifying compounds for Parkinson's disease have typically been based on toxin-induced in vitro and in vivo models of this neurodegenerative condition. All these compounds have failed to have a reliable disease-modifying effect in subsequent clinical trials. We have now established a novel approach, namely to screen an entire compound library directly in patient tissue to identify compounds with a rescue effect on mitochondrial dysfunction as a crucial pathogenic mechanism in Parkinson's disease. The chosen Microsource Compound library contains 2000 compounds, including 1040 licensed drugs and 580 naturally occurring compounds. All 2000 compounds were tested in a step-wise approach for their rescue effect on mitochondrial dysfunction in parkin (PARK2) mutant fibroblasts. Of 2000 compounds, 60 improved the mitochondrial membrane potential by at least two standard deviations. Subsequently, these 60 compounds were assessed for their toxicity and drug-like dose-response. The remaining 49 compounds were tested in a secondary screen for their rescue effect on intracellular ATP levels. Of 49 compounds, 29 normalized ATP levels and displayed drug-like dose response curves. The mitochondrial rescue effect was confirmed for 15 of these 29 compounds in parkin-mutant fibroblasts from additional patients not included in the initial screen. Of 15 compounds, two were chosen for subsequent functional studies, namely ursocholanic acid and the related compound dehydro(11,12)ursolic acid lactone. Both compounds markedly increased the activity of all four complexes of the mitochondrial respiratory chain. The naturally occurring compound ursolic acid and the licensed drug ursodeoxycholic acid are chemically closely related to ursocholanic acid and dehydro(11,12)ursolic acid lactone. All four substances rescue mitochondrial function to a similar extent in parkin-mutant fibroblasts, suggesting a class effect. The mitochondrial rescue effect depends on activation of the glucocorticoid receptor with increased phosphorylation of Akt and was confirmed for both ursocholanic acid and ursodeoxycholic acid in a Parkin-deficient neuronal model system. Of note, both ursocholanic acid and ursodeoxycholic acid also rescued mitochondrial function in LRRK2(G2019S) mutant fibroblasts. Our study demonstrates the feasibility of undertaking drug screens in Parkinson's disease patients' tissue and has identified a group of chemically-related compounds with marked mitochondrial rescue effect. Drug repositioning is considered to be a time- and cost-saving strategy to assess drugs already licensed for a different condition for their neuroprotective effect. We therefore propose both ursolic acid as a naturally occurring compound, and ursodeoxycholic acid as an already licensed drug as promising compounds for future neuroprotective trials in Parkinson's disease.
authors.affiliation: 1 Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK.
authors.forename: Heather
authors.initials: H
authors.lastname: Mortiboys
authors.forename: Jan
authors.initials: J
authors.lastname: Aasly
authors.forename: Oliver
authors.initials: O
authors.lastname: Bandmann
mesh_terms: D000328:Adult; D002793:Cholic Acids / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics; D014580:Ursodeoxycholic Acid / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D002793:Cholic Acids; D014580:Ursodeoxycholic Acid; C007036:cholanic acid
keywords: LRRK2; Parkinson’s disease; disease-modifying therapy; mitochondria; parkin