PubMed:26931464 JSONTXT

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protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity.\nParkinson's disease (PD) is a progressive neurodegenerative disorder that lacks a disease-modifying therapy. Leucine-rich repeat kinase 2 (LRRK2) was implicated as the most common genetic cause of PD. We previously established a LRRK2-G2019S Drosophila model that displayed the crucial phenotypes of LRRK2 parkinsonism. Here, we used a two-step approach to identify compounds from the FDA-approved licensed drug library that could suppress neurite degeneration in LRRK2-G2019S parkinsonism. Of 640 compounds, 29 rescued neurite degeneration phenotypes and 3 restored motor disability and dopaminergic neuron loss in aged LRRK2-G2019S flies. Of these three drugs, lovastatin had the highest lipophilicity, which facilitated crossing the blood-brain barrier. In LRRK2-G2019S knock-in mice and stably transfected human dopaminergic cells, lovastatin significantly rescued neurite degeneration in a dose-dependent manner, within a range of 0.05-0.1 μm The beneficial effect of lovastatin was exerted by activating anti-apoptotic Akt/Nrf signaling and decreasing caspase 3 levels. We also observed that lovastatin inhibited GSK3β activity, a kinase downstream of Akt, by up-regulating GSK3β (Ser9) phosphorylation. This inhibition subsequently decreased tau phosphorylation, which was linked to neuronal cytoskeleton instability. Conversely, pre-treatment with the Akt inhibitor, A6730, blocked the lovastatin-induced neuroprotective effect. The rescuing effects of lovastatin in dendritic arborization of LRRK2-G2019S neurons were abolished by co-expressing either a mutant allele of Akt (Akt1(04226)) or a constitutively active form of GSK3β (sgg(S9A)). Our findings demonstrated that lovastatin restored LRRK2-G2019S neurite degeneration by augmenting Akt/NRF2 pathway and inhibiting downstream GSK3β activity, which decreased phospho-tau levels. We suggested that lovastatin is a potential disease-modifying agent for LRRK2-G2019S parkinsonism."}

{"project":"PubMed_ArguminSci","denotations":[{"id":"T1","span":{"begin":140,"end":248},"obj":"DRI_Background"},{"id":"T2","span":{"begin":249,"end":340},"obj":"DRI_Approach"},{"id":"T3","span":{"begin":341,"end":459},"obj":"DRI_Approach"},{"id":"T4","span":{"begin":460,"end":630},"obj":"DRI_Approach"},{"id":"T5","span":{"begin":631,"end":780},"obj":"DRI_Background"},{"id":"T6","span":{"begin":781,"end":896},"obj":"DRI_Approach"},{"id":"T7","span":{"begin":897,"end":899},"obj":"DRI_Background"},{"id":"T8","span":{"begin":922,"end":1215},"obj":"DRI_Background"},{"id":"T9","span":{"begin":1216,"end":1305},"obj":"DRI_Approach"},{"id":"T10","span":{"begin":1326,"end":1349},"obj":"DRI_Approach"},{"id":"T11","span":{"begin":1350,"end":1464},"obj":"DRI_Background"},{"id":"T12","span":{"begin":1465,"end":1576},"obj":"DRI_Approach"},{"id":"T13","span":{"begin":1577,"end":1790},"obj":"DRI_Background"},{"id":"T14","span":{"begin":1791,"end":1984},"obj":"DRI_Outcome"},{"id":"T15","span":{"begin":1985,"end":2083},"obj":"DRI_Approach"}],"text":"Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity.\nParkinson's disease (PD) is a progressive neurodegenerative disorder that lacks a disease-modifying therapy. Leucine-rich repeat kinase 2 (LRRK2) was implicated as the most common genetic cause of PD. We previously established a LRRK2-G2019S Drosophila model that displayed the crucial phenotypes of LRRK2 parkinsonism. Here, we used a two-step approach to identify compounds from the FDA-approved licensed drug library that could suppress neurite degeneration in LRRK2-G2019S parkinsonism. Of 640 compounds, 29 rescued neurite degeneration phenotypes and 3 restored motor disability and dopaminergic neuron loss in aged LRRK2-G2019S flies. Of these three drugs, lovastatin had the highest lipophilicity, which facilitated crossing the blood-brain barrier. In LRRK2-G2019S knock-in mice and stably transfected human dopaminergic cells, lovastatin significantly rescued neurite degeneration in a dose-dependent manner, within a range of 0.05-0.1 μm The beneficial effect of lovastatin was exerted by activating anti-apoptotic Akt/Nrf signaling and decreasing caspase 3 levels. We also observed that lovastatin inhibited GSK3β activity, a kinase downstream of Akt, by up-regulating GSK3β (Ser9) phosphorylation. This inhibition subsequently decreased tau phosphorylation, which was linked to neuronal cytoskeleton instability. Conversely, pre-treatment with the Akt inhibitor, A6730, blocked the lovastatin-induced neuroprotective effect. The rescuing effects of lovastatin in dendritic arborization of LRRK2-G2019S neurons were abolished by co-expressing either a mutant allele of Akt (Akt1(04226)) or a constitutively active form of GSK3β (sgg(S9A)). Our findings demonstrated that lovastatin restored LRRK2-G2019S neurite degeneration by augmenting Akt/NRF2 pathway and inhibiting downstream GSK3β activity, which decreased phospho-tau levels. We suggested that lovastatin is a potential disease-modifying agent for LRRK2-G2019S parkinsonism."}