Journal
JOURNAL OF NEUROSCIENCE
Volume 29, Issue 4, Pages 1011-1016Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5175-08.2009
Keywords
Parkinson's disease; apoptosis; neuronal apoptosis; neuronal death; neuron death; caspase
Categories
Funding
- National Institutes of Neurological Disorders and Stroke [K02 NS045798, R01 NS061098]
- Parkinson Disease Foundation
- Anne and Bernard Spitzer Center for Cell and Genetic Therapy for Parkinson Disease
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available