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UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo.
Neurology 2015; 85(10):846-52Neur

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.

CONCLUSION

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+Show Affiliations

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.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.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26253449

Citation

Mortiboys, Heather, et al. "UDCA Exerts Beneficial Effect On Mitochondrial Dysfunction in LRRK2(G2019S) Carriers and in Vivo." Neurology, vol. 85, no. 10, 2015, pp. 846-52.
Mortiboys H, Furmston R, Bronstad G, et al. UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. Neurology. 2015;85(10):846-52.
Mortiboys, H., Furmston, R., Bronstad, G., Aasly, J., Elliott, C., & Bandmann, O. (2015). UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. Neurology, 85(10), pp. 846-52. doi:10.1212/WNL.0000000000001905.
Mortiboys H, et al. UDCA Exerts Beneficial Effect On Mitochondrial Dysfunction in LRRK2(G2019S) Carriers and in Vivo. Neurology. 2015 Sep 8;85(10):846-52. PubMed PMID: 26253449.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2(G2019S) carriers and in vivo. AU - Mortiboys,Heather, AU - Furmston,Rebecca, AU - Bronstad,Gunnar, AU - Aasly,Jan, AU - Elliott,Chris, AU - Bandmann,Oliver, Y1 - 2015/08/07/ PY - 2014/03/13/received PY - 2015/03/09/accepted PY - 2015/8/9/entrez PY - 2015/8/9/pubmed PY - 2015/12/15/medline SP - 846 EP - 52 JF - Neurology JO - Neurology VL - 85 IS - 10 N2 - 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. CONCLUSION: 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. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/26253449/UDCA_exerts_beneficial_effect_on_mitochondrial_dysfunction_in_LRRK2_G2019S__carriers_and_in_vivo_ L2 - http://www.neurology.org/cgi/pmidlookup?view=long&pmid=26253449 DB - PRIME DP - Unbound Medicine ER -