https://scholars.lib.ntu.edu.tw/handle/123456789/463628
標題: | Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity | 作者: | CHIN-HSIEN LIN Lin H.-I. Chen M.-L. Lai T.-T. Cao L.-P. Farrer M.J. RUEY-MEEI WU Chien C.-T. |
公開日期: | 15-五月-2016 | 卷: | 25 | 期: | 10 | 起(迄)頁: | 1965 | 來源出版物: | Human Molecular Genetics | 摘要: | 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. ? The Author 2016. Published by Oxford University Press. All rights reserved. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/463628 | ISSN: | 0964-6906 | DOI: | 10.1093/hmg/ddw068 | SDG/關鍵字: | glycogen synthase kinase 3beta; leucine rich repeat kinase 2; mevinolin; protein kinase B; transcription factor Nrf2; glycogen synthase kinase 3beta; HABP2 protein, human; leucine rich repeat kinase 2; mevinolin; protein kinase B; serine proteinase; adult; allele; animal cell; Article; blood brain barrier; cell counting; controlled study; dendrite; dopaminergic nerve cell; Drosophila; enzyme activity; human; human cell; mouse; nerve degeneration; neuroprotection; nonhuman; parkinsonism; phenotype; priority journal; protein expression; signal transduction; animal; antagonists and inhibitors; biosynthesis; Drosophila melanogaster; drug effects; genetics; motoneuron; mutation; nerve degeneration; neurite; Parkinson disease; Parkinsonian Disorders; pathology; pathophysiology; transgenic animal; Animals; Animals, Genetically Modified; Dopaminergic Neurons; Drosophila melanogaster; Glycogen Synthase Kinase 3 beta; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Lovastatin; Mice; Motor Neurons; Mutation; Nerve Degeneration; Neurites; Parkinson Disease; Parkinsonian Disorders; Proto-Oncogene Proteins c-akt; Serine Endopeptidases; Signal Transduction |
顯示於: | 醫學系 |
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