Parkinson's disease (PD) is a
neurodegenerative disorder in which genetic and environmental factors synergistically lead to loss of midbrain
dopamine (DA) neurons. Mutation of
leucine-rich repeated kinase2 (Lrrk2) genes is responsible for the majority of inherited familial cases of PD and can also be found in sporadic cases. The pathophysiological role of this
kinase has to be fully understood yet. Hyperactivation of Lrrk2
kinase domain might represent a predisposing factor for both enhanced striatal glutamatergic release and mitochondrial vulnerability to environmental factors that are observed in PD. To investigate possible alterations of striatal susceptibility to
mitochondrial dysfunction, we performed electrophysiological recordings from the nucleus striatum of a G2019S Lrrk2 mouse model of PD, as well as molecular and morphological analyses of G2019S Lrrk2-expressing SH-SY5Y
neuroblastoma cells. In G2019S mice, we found reduced striatal DA levels, according to the hypothesis of alteration of dopaminergic transmission, and increased loss of field potential induced by the mitochondrial complex I inhibitor
rotenone. This detrimental effect is reversed by the D2 DA receptor agonist
quinpirole via the inhibition of the cAMP/PKA intracellular pathway. Analysis of mitochondrial functions in G2019S Lrrk2-expressing SH-SY5Y cells revealed strong
rotenone-induced oxidative stress characterized by reduced Ca2+ buffering capability and
ATP synthesis, production of
reactive oxygen species, and increased mitochondrial fragmentation. Importantly,
quinpirole was able to prevent all these changes. We suggest that the G2019S-Lrrk2 mutation is a predisposing factor for enhanced striatal susceptibility to
mitochondrial dysfunction induced by exposure to mitochondrial environmental toxins and that the D2 receptor stimulation is neuroprotective on mitochondrial function, via the inhibition of cAMP/PKA intracellular pathway. We suggest new possible neuroprotective strategies for patients carrying this genetic alteration based on drugs specifically targeting Lrrk2
kinase domain and mitochondrial functionality.