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September 08, 2015; 85 (10) Article

UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo

Heather Mortiboys, Rebecca Furmston, Gunnar Bronstad, Jan Aasly, Chris Elliott and Oliver Bandmann
First published August 7, 2015, DOI: https://doi.org/10.1212/WNL.0000000000001905
Heather Mortiboys
From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway.
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Rebecca Furmston
From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway.
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Gunnar Bronstad
From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway.
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Jan Aasly
From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway.
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Chris Elliott
From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway.
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Oliver Bandmann
From the Sheffield Institute for Translational Neuroscience (SITraN) (H.M., O.B.), University of Sheffield; the Department of Biology (R.F., C.E.), University of York, UK; Neurozym Biotech AS (G.B.), Snaasa; and the Department of Neurology (J.A.), St Olav's Hospital, Trondheim, Norway.
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UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo
Heather Mortiboys, Rebecca Furmston, Gunnar Bronstad, Jan Aasly, Chris Elliott, Oliver Bandmann
Neurology Sep 2015, 85 (10) 846-852; DOI: 10.1212/WNL.0000000000001905

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Abstract

Objective: To further characterize mitochondrial dysfunction in LRRK2G2019S mutant Parkinson disease (PD) patient tissue (M-LRRK2G2019S), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2G2019S mutation carriers (NM-LRRK2G2019S), and assess UDCA for its beneficial effect on neuronal dysfunction in vivo.

Methods: Intracellular adenosine 5′-triphosphate (ATP) levels, oxygen consumption, and activity of the individual complexes of the mitochondrial respiratory chain as well as mitochondrial morphology were measured in M-LRRK2G2019S, NM-LRRK2G2019S, and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2G2019S and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2G2019S.

Results: Crucial parameters of mitochondrial function were similarly reduced in both M-LRRK2G2019S and NM-LRRK2G2019S with a specific decrease in respiratory chain complex IV activity. Mitochondrial dysfunction precedes changes in mitochondrial morphology but is normalized after siRNA-mediated knockdown of LRRK2. UDCA improved mitochondrial function in NM-LRRK2G2019 and rescued the loss of visual function in LRRK2G2019S flies.

Conclusion: There is clear preclinical impairment of mitochondrial function in NM-LRRK2G2019S that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2G2019S and M-LRRK2G2019S as well as on the function of dopaminergic neurons expressing LRRK2G2019S suggests that UDCA is a promising drug for future neuroprotective trials.

GLOSSARY

ANOVA=
analysis of variance;
ATP=
adenosine 5′-triphosphate;
CRF=
contrast response function;
EOPD=
early-onset Parkinson disease;
FDA=
Food and Drug Administration;
M-LRRK2G2019S=
manifesting LRRK2G2019S carriers;
NM-LRRK2G2019S=
nonmanifesting LRRK2G2019S carriers;
PD=
Parkinson disease;
SSVEP=
steady-state visual evoked potentials;
TUDCA=
taurine conjugate;
UDCA=
ursodeoxycholic acid

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • ↵* These authors contributed equally as joint first authors.

  • ↵‡ These authors contributed equally as joint last authors.

  • Supplemental data at Neurology.org

  • Editorial, page 838

  • Received March 13, 2014.
  • Accepted in final form March 9, 2015.
  • © 2015 American Academy of Neurology
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