Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death

Dario C. Angeles, Bong Hwa Gan, Luisa Onstead, Yi Zhao, Kah Leong Lim, Justus Dachsel, Heather L Melrose, Matt Farrer, Zbigniew K Wszolek, Dennis W Dickson, Eng King Tan

Research output: Contribution to journalArticle

59 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1390-1397
Number of pages8
JournalHuman Mutation
Volume32
Issue number12
DOIs
StatePublished - Dec 2011

Fingerprint

Peroxiredoxin III
Leucine
Oxidative Stress
Phosphotransferases
Phosphorylation
Mutation
Parkinson Disease
Peroxidase
Peroxiredoxins
Poisons

Keywords

  • Apoptosis
  • LRRK2
  • Oxidative damage
  • Peroxiredoxin 3
  • Phosphorylation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Angeles, D. C., Gan, B. H., Onstead, L., Zhao, Y., Lim, K. L., Dachsel, J., ... Tan, E. K. (2011). Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. Human Mutation, 32(12), 1390-1397. https://doi.org/10.1002/humu.21582

Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. / Angeles, Dario C.; Gan, Bong Hwa; Onstead, Luisa; Zhao, Yi; Lim, Kah Leong; Dachsel, Justus; Melrose, Heather L; Farrer, Matt; Wszolek, Zbigniew K; Dickson, Dennis W; Tan, Eng King.

In: Human Mutation, Vol. 32, No. 12, 12.2011, p. 1390-1397.

Research output: Contribution to journalArticle

Angeles, DC, Gan, BH, Onstead, L, Zhao, Y, Lim, KL, Dachsel, J, Melrose, HL, Farrer, M, Wszolek, ZK, Dickson, DW & Tan, EK 2011, 'Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death', Human Mutation, vol. 32, no. 12, pp. 1390-1397. https://doi.org/10.1002/humu.21582
Angeles, Dario C. ; Gan, Bong Hwa ; Onstead, Luisa ; Zhao, Yi ; Lim, Kah Leong ; Dachsel, Justus ; Melrose, Heather L ; Farrer, Matt ; Wszolek, Zbigniew K ; Dickson, Dennis W ; Tan, Eng King. / Mutations in LRRK2 increase phosphorylation of peroxiredoxin 3 exacerbating oxidative stress-induced neuronal death. In: Human Mutation. 2011 ; Vol. 32, No. 12. pp. 1390-1397.
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