Liver Drug Studied as Potential Parkinson’s Treatment

A drug used for treating liver disease shows potential as a therapy for slowing the progression of a genetic form of Parkinson’s disease (PD), according to research published in the August 7 online edition of Neurology. In experiments with cells and fruit flies, the drug reversed cellular damage caused by a mutation in the LRRK2 (leucine-rich repeat kinase 2) gene.

Genetic mutations cause PD in a small percentage of cases, but among those, mutations in the gene known as LRRK2 are among the most common. In some instances, LRRK2 mutations are passed down within a family, causing PD in many members. But LRRK2 mutations are also present in people without a family history of PD, and this puts those individuals at a higher risk of developing PD.

It is unknown how mutations in LRRK2 cause PD, but one hypothesis is that mutations in LRRK2 damage the mitochondria within cells — the “power plants” that provide cells with energy. For the new study, researchers led by Oliver Bandmann, M.D., Ph.D., at the University of Sheffield, United Kingdom, measured how well mitochondria worked in skin cells from 15 people: five who had both a LRRK2 mutation and PD, five with the LRRK2 mutation who did not have PD, and five with neither a LRRK2 mutation nor PD. Then they treated the cells with a drug called, ursodeoxycholic acid (UDCA), which has long been used for a variety of liver diseases, and again assessed how well the cells’ mitochondria were working. In another experiment, they fed the same drug, UDCA, to fruit flies with a LRRK2mutation. In these flies, the LRRK2 mutation affects nerve cells and causes vision loss.

Results

  • In cells from people with the LRRK2 mutation, mitochondria were damaged whether or not they had PD, indicating that changes to mitochondria can occur independent of PD symptoms.
  • Cells from people in both those with and without PD had decreased levels of cellular energy.
  • The impairment to mitochondria in cells from people with the LRRK2 mutation was different from that seen previously in people with mutations in another gene, known as Parkin, which causes PD.
  • When cells from people with the LRRK2 mutation, with or without PD, were treated with UDCA, the mitochondria began producing more energy.
  • After fruit flies with the LRRK2 mutation ate the UDCA, vision damage caused by the mutation improved.

What Does It Mean?

An important finding of this study is that cells from people who carried the LRRK2 mutation had damaged mitochondria, even without having PD symptoms. The liver drug UDCA helped to repair the damage in the cells grown in the laboratory. The study authors suggest that treatment strategies that help to rescue mitochondria from damage may be a possible avenue for treating people with LRRK2-related PD — either alone or in combination with drugs that might target mutated LRRK2 proteins directly.

The authors conclude that this early-stage investigation suggests that UDCA should be studied further for its neuroprotective effects — its potential to protect against cellular changes that underlie PD even before symptoms develop in people with the LRRK2 mutation. Because UDCA is a drug already approved by the US Food and Drug Administration, and has been shown to be safe, future clinical trials to test its effectiveness for people with PD, or at risk for PD, could proceed sooner than they would for a new drug whose safety was unknown.

Reference

Mortiboys H, Furmston R, Bronstad G, Aasly J, Elliott C, Bandmann O. UDCA Exerts Beneficial Effect on Mitochondrial Dysfunction in LRRK2G2019SCarriers and In Vivo. Neurology (2015) 85:1–8. http://doi.org/10.1212/WNL.0000000000001905

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