title: UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo.
abstract: OBJECTIVE
  To further characterize mitochondrial dysfunction in LRRK2(G2019S) mutant Parkinson disease (PD) patient tissue (M-LRRK2(G2019S)), determine whether ursodeoxycholic acid (UDCA) also exerts a beneficial effect on mitochondrial dysfunction in nonmanifesting LRRK2(G2019S) mutation carriers (NM-LRRK2(G2019S)), 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-LRRK2(G2019S), NM-LRRK2(G2019S), and controls. UDCA was assessed for its rescue effect on intracellular ATP levels in NM-LRRK2(G2019S) and in a LRRK2 transgenic fly model with dopaminergic expression of LRRK2(G2019S).
  
  
  RESULTS
  Crucial parameters of mitochondrial function were similarly reduced in both M-LRRK2(G2019S) and NM-LRRK2(G2019S) 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-LRRK2(G2019) and rescued the loss of visual function in LRRK2(G2019S) flies.
  
  
  CONCLUSIONS
  There is clear preclinical impairment of mitochondrial function in NM-LRRK2(G2019S) that is distinct from the mitochondrial impairment observed in parkin-related PD. The beneficial effect of UDCA on mitochondrial function in both NM-LRRK2(G2019S) and M-LRRK2(G2019S) as well as on the function of dopaminergic neurons expressing LRRK2(G2019S) suggests that UDCA is a promising drug for future neuroprotective trials.
authors.affiliation: 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.
authors.forename: Heather
authors.initials: H
authors.lastname: Mortiboys
authors.affiliation: 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.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Furmston
authors.affiliation: 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.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Bronstad
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Aasly
authors.affiliation: 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.
authors.forename: Chris
authors.initials: C
authors.lastname: Elliott
authors.affiliation: 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. o.bandmann@sheffield.ac.uk.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bandmann
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila; D005260:Female; D006579:Heterozygote; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D014580:Ursodeoxycholic Acid; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases