title: Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death.
abstract: Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are responsible for autosomal dominant and sporadic Parkinson disease (PD), possibly exerting their effects via a toxic gain of function. A common p.G2019S mutation (rs34637584:A>G) is responsible for up to 30-40% of PD cases in some ethnic populations. Here, we show that LRRK2 interacts with human peroxiredoxin 3 (PRDX3), a mitochondrial member of the antioxidant family of thioredoxin (Trx) peroxidases. Importantly, mutations in the LRRK2 kinase domain significantly increased phosphorylation of PRDX3 compared to wild-type. The increase in PRDX3 phosphorylation was associated with decreased peroxidase activity and increased death in LRRK2-expressing but not in LRRK2-depleted or vector-transfected neuronal cells. LRRK2 mutants stimulated mitochondrial factors involved in apoptosis and induced production of reactive oxygen species (ROS) and oxidative modification of macromolecules. Furthermore, immunoblot and immunohistochemical analysis of postmortem human PD patients carrying the p.G2019S mutation showed a marked increase in phosphorylated PRDX3 (p-PRDX3) relative to normal brain. We showed that LRRK2 mutations increase the inhibition of an endogenous peroxidase by phosphorylation promoting dysregulation of mitochondrial function and oxidative damage. Our findings provide a mechanistic link between the enhanced kinase activity of PD-linked LRRK2 and neuronal cell death.
authors.affiliation: Neuroscience Laboratory, Singapore Health Services Research Facilities, Singapore.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Angeles
authors.forename: Bong-Hwa
authors.initials: BH
authors.lastname: Gan
authors.forename: Luisa
authors.initials: L
authors.lastname: Onstead
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Kah-Leong
authors.initials: KL
authors.lastname: Lim
authors.forename: Justus
authors.initials: J
authors.lastname: Dachsel
authors.forename: Heather
authors.initials: H
authors.lastname: Melrose
authors.forename: Matt
authors.initials: M
authors.lastname: Farrer
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Eng-King
authors.initials: EK
authors.lastname: Tan
mesh_terms: D016923:Cell Death; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress / Q000235:genetics* / Q000502:physiology; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D061105:Peroxiredoxin III / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D061105:Peroxiredoxin III; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases