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The Journal of Neuroscience, January 28, 2009, 29(4):1011-1016; doi:10.1523/JNEUROSCI.5175-08.2009

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Brief Communications
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

Cherry Cheng-Ying Ho,^1,2 Hardy J. Rideout,² Elena Ribe,¹ Carol M. Troy,^1,2,4 and William T. Dauer^2,3

Departments of ¹Pathology, ²Neurology, and ³Pharmacology, and ⁴Taub Center for the Study of Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York 10032

Correspondence should be addressed to William Dauer, Columbia University, 650 West 168th Street, Room 310, New York, NY 10032. Email: wtd3{at}columbia.edu

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.

Key words: Parkinson's disease; apoptosis; neuronal apoptosis; neuronal death; neuron death; caspase

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Received Oct. 26, 2008; revised Nov. 17, 2008; accepted Dec. 16, 2008.

Correspondence should be addressed to William Dauer, Columbia University, 650 West 168th Street, Room 310, New York, NY 10032. Email: wtd3{at}columbia.edu

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