Lovastatin protects neurite degeneration in LRRK2-G2019S parkinsonism through activating the Akt/Nrf pathway and inhibiting GSK3β activity

Hum Mol Genet. 2016 May 15;25(10):1965-1978. doi: 10.1093/hmg/ddw068. Epub 2016 Feb 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / pathology
  • Drosophila melanogaster / genetics
  • Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 beta / biosynthesis
  • Glycogen Synthase Kinase 3 beta / genetics*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Lovastatin / administration & dosage
  • Mice
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Mutation
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Neurites / drug effects
  • Parkinson Disease / drug therapy
  • Parkinson Disease / genetics*
  • Parkinson Disease / pathology
  • Parkinsonian Disorders / drug therapy
  • Parkinsonian Disorders / genetics
  • Parkinsonian Disorders / physiopathology
  • Proto-Oncogene Proteins c-akt / genetics*
  • Serine Endopeptidases / genetics*
  • Signal Transduction / drug effects


  • Lovastatin
  • Glycogen Synthase Kinase 3 beta
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Proto-Oncogene Proteins c-akt
  • HABP2 protein, human
  • Serine Endopeptidases