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

TY - JOUR

T1 - UDCA exerts beneficial effect on mitochondrial dysfunction in LRRK2G2019S carriers and in vivo

AU - Mortiboys, Heather

AU - Furmston, Rebecca

AU - Bronstad, Gunnar

AU - Aasly, Jan

AU - Elliott, Chris

AU - Bandmann, Oliver

N1 - © 2015 American Academy of Neurology.

PY - 2015/9/8

Y1 - 2015/9/8

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.

AB - 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.

U2 - 10.1212/WNL.0000000000001905

DO - 10.1212/WNL.0000000000001905

M3 - Article

C2 - 26253449

SN - 0028-3878

VL - 85

SP - 846

EP - 852

JO - Neurology

JF - Neurology

IS - 10

ER -