title: Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity.
abstract: Parkinson'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 (Akt104226) or a constitutively active form of GSK3β (sggS9A). 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.
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine and chlin@ntu.edu.tw.
authors.forename: Chin-Hsien
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine and.
authors.forename: Han-I
authors.initials: HI
authors.lastname: Lin
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine and Department of Life Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Meng-Ling
authors.initials: ML
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital Yun-Lin Branch, Yun-Lin, Taiwan.
authors.forename: Tzu-Ting
authors.initials: TT
authors.lastname: Lai
authors.affiliation: Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada and.
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Cao
authors.affiliation: Centre for Applied Neurogenetics, University of British Columbia, Vancouver, Canada and.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Farrer
authors.affiliation: Department of Neurology, National Taiwan University Hospital, College of Medicine and.
authors.forename: Ruey-Meei
authors.initials: RM
authors.lastname: Wu
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Cheng-Ting
authors.initials: CT
authors.lastname: Chien
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology; D004331:Drosophila melanogaster / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D008148:Lovastatin / Q000008:administration & dosage; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016501:Neurites / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D008148:Lovastatin; D000071679:Glycogen Synthase Kinase 3 beta; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051057:Proto-Oncogene Proteins c-akt; C433550:HABP2 protein, human; D012697:Serine Endopeptidases