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.
We provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson's disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest. As such we observe four unique opportunities provided by fly nervous system models of Parkinson's disease. Firstly, Drosophila models are instrumental in exploring the mechanisms of neurodegeneration, with several PD-related mutations eliciting related phenotypes including sensitivity to energy supply and vesicular deformities. These are leading to the identification of plausible cellular mechanisms, which may be specific to (dopaminergic) neurons and synapses rather than general cellular phenotypes. Secondly, models show noncell autonomous signalling within the nervous system, offering the opportunity to develop our understanding of the way pathogenic signalling propagates, resembling Braak's scheme of spreading pathology in PD. Thirdly, the models link physiological deficits to changes in synaptic structure. While the structure-function relationship is complex, the genetic tractability of Drosophila offers the chance to separate fundamental changes from downstream consequences. Finally, the strong neuronal phenotypes permit relevant first in vivo drug testing.
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