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The Parkinson disease protein leucine-rich repeat kinase 2 transduces death signals via Fas-associated protein with death domain and caspase-8 in a cellular model of neurodegeneration.

Neurodegenerative illnesses such as Parkinson and Alzheimer disease are an increasingly prevalent problem in aging societies, yet no therapies exist that retard or prevent neurodegeneration. Dominant missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson disease (PD), but the mechanisms by which mutant forms of LRRK2 disrupt neuronal function and cause cell death remain poorly understood. We report that LRRK2 interacts with the death adaptor Fas-associated protein with death domain (FADD), and that in primary neuronal culture LRRK2-mediated neurodegeneration is prevented by the functional inhibition of FADD or depletion of caspase-8, two key elements of the extrinsic cell death pathway. This pathway is activated by disease-triggering mutations, which enhance the LRRK2-FADD association and the consequent recruitment and activation of caspase-8. These results establish a direct molecular link between a mutant PD gene and the activation of programmed cell death signaling, and suggest that FADD/caspase-8 signaling contributes to LRRK2-induced neuronal death.

Pubmed ID: 19176810

Authors

  • Ho CC
  • Rideout HJ
  • Ribe E
  • Troy CM
  • Dauer WT

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

January 28, 2009

Associated Grants

  • Agency: NINDS NIH HHS, Id: K02 NS045798
  • Agency: NINDS NIH HHS, Id: K02 NS045798
  • Agency: NINDS NIH HHS, Id: K02 NS045798-01A1
  • Agency: NINDS NIH HHS, Id: R01 NS061098
  • Agency: NINDS NIH HHS, Id: R01 NS061098
  • Agency: NINDS NIH HHS, Id: R01 NS061098-01A1

Mesh Terms

  • Apoptosis
  • Carrier Proteins
  • Caspase 8
  • Cell Line, Transformed
  • Fas-Associated Death Domain Protein
  • Green Fluorescent Proteins
  • Humans
  • Mutagenesis, Site-Directed
  • Neurons
  • Protein-Serine-Threonine Kinases
  • RNA, Small Interfering
  • Transfection