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

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 onmitochondrial 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-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 MLRRK2(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) andM-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.