But what is the consequence of this excess signaling? Multiple lines of evidence suggest LRRK2 may increase apoptosis through its interaction with a protein called FADD. All disease-causing mutations enhance the interaction of the two, and this interaction is blocked by inhibiting the kinase activity of LRRK2. FADD is known to work within a specific cell death pathway, which ends with activation of the enzyme caspase-8. Dr. Dauer has shown that blocking FADD function or depleting the supply of caspase-8 blocks neurodegeneration in vitro. “These results suggest that activation of caspase-8 is a pathogenic event in Parkinson’s disease,” he said. Current investigations include determining whether caspase-8 activity is elevated in the brains of patients who died with LRRK2 Parkinson’s disease. So far, he has seen some tantalizing evidence that this may be so, while it is not the case for patients with non-LRRK2 Parkinson’s disease. “We still need to explore whether idiopathic disease activates this pathway,” he added.
“Our current model is that disease mutations in LRRK2 enhance oligomerization, which leads to recruitment of FADD, which leads to a toxic signal. This could be a general mechanism, beyond FADD and caspase-8,” concluded Dr. Dauer. He noted that more work is needed to incorporate kinase-enhancing mutations within this model. Future studies will also investigate how the pathogenic cascade of LRRK2 relates to that in sporadic forms of the disease and how these insights may be used to develop therapies.
—Richard Robinson