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 59-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-LRRK2 G2019S , 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 LRRK2 G2019S .Results: Crucial parameters of mitochondrial function were similarly reduced in both M- LRRK2G2019S 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 G2019Sthat 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. G2019S 5 manifesting LRRK2 G2019S carriers; NM-LRRK2 G2019S 5 nonmanifesting LRRK2 G2019S carriers; PD 5 Parkinson disease; SSVEP 5 steady-state visual evoked potentials; TUDCA 5 taurine conjugate; UDCA 5 ursodeoxycholic acid.

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