Abstract
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.
Highlights
Leucine-rich repeat kinase 2 (Lrrk2) is a large protein with a GTPase, kinase, and scaffolding domain, implicated in a wide range of diseases[1]
We explored the effect of rotenone, a mitochondrial complex I inhibitor known to induce progressive striatal neurodegeneration with a dose-dependent effect[28,29,30], on striatal slices of mice expressing the G2019S Lrrk[2] mutation (KI)
In WT mice, exposure of the slices to forskolin enhanced the detrimental effect of rotenone (Fig. 3b), to what was observed in slices of KI mice treated with rotenone (Fig. 1a). These results suggest that the neuroprotective effect of quinpirole on mitochondrial complex I impairment in G2019S KI mice is mediated by inhibition of the cAMP/ PKA intracellular pathway
Summary
Leucine-rich repeat kinase 2 (Lrrk2) is a large protein with a GTPase, kinase, and scaffolding domain, implicated in a wide range of diseases[1]. Mutations in Lrrk[2] are recognized as genetic risk. Tozzi et al Cell Death and Disease (2018)9:204. Exposure to chronic pesticides, such as the mitochondrial complex I inhibitor rotenone, may enhance the possibility to develop PD6,7. This neurotoxin has been extensively used to model PD8–10. Exposure to rotenone may speed up neurodegenerative processes triggered by Lrrk[2] mutations by directly affecting mitochondrial homeostasis[12]. Mitochondrial functions (i.e., oxidative phosphorylation, Ca2+ buffering, and control of reactive radical species) are inhibited by toxins targeting mitochondrial complexes, and may lead to irreversible neuronal membrane changes, molecular alterations, and possibly to cell death
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