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.
Ho
Cherry Cheng-Ying
CC
Department of Pathology, Columbia University, New York, New York 10032, USA.
Rideout
Hardy J
HJ
Ribe
Elena
E
Troy
Carol M
CM
Dauer
William T
WT
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics; D053181:Caspase 8 / Q000378:metabolism*; D002461:Cell Line, Transformed; D057846:Cell-Penetrating Peptides; D053200:Fas-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection / Q000379:methods
D002352:Carrier Proteins; D057846:Cell-Penetrating Peptides; D053200:Fas-Associated Death Domain Protein; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; C414409:penetratin; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; D053181:Caspase 8