@article{3178915,
    title = "A motif within the armadillo repeat of Parkinson's-linked LRRK2
interacts with FADD to hijack the extrinsic death pathway",
    author = "Antoniou, Nasia and Vlachakis, Dimitrios and Memou, Anna and Leandrou, and Emmanouela and Valkimadi, Polytimi-Eleni and Melachroinou, Katerina and and Re, Diane B. and Przedborski, Serge and Dauer, William T. and Stefanis, and Leonidas and Rideout, Hardy J.",
    journal = "Scientific Reports",
    year = "2018",
    volume = "8",
    publisher = "Nature Publishing Group",
    issn = "2045-2322",
    doi = "10.1038/s41598-018-21931-8",
    abstract = "In experimental models, both in vivo and cellular, over-expression of
Parkinson's linked mutant leucine-rich repeat kinase 2 (LRRK2) is
sufficient to induce neuronal death. While several cell death associated
proteins have been linked to LRRK2, either as protein interactors or as
putative substrates, characterization of the neuronal death cascade
remains elusive. In this study, we have mapped for the first time the
domain within LRRK2 that mediates the interaction with FADD, thereby
activating the molecular machinery of the extrinsic death pathway. Using
homology modeling and molecular docking approaches, we have identified a
critical motif within the N-terminal armadillo repeat region of LRRK2.
Moreover, we show that co-expression of fragments of LRRK2 that contain
the FADD binding motif, or deletion of this motif itself, blocks the
interaction with FADD, and is neuroprotective. We further demonstrate
that downstream of FADD, the mitochondrial proteins Bid and Bax are
recruited to the death cascade and are necessary for neuronal death. Our
work identifies multiple novel points within neuronal death signaling
pathways that could potentially be targeted by candidate therapeutic
strategies and highlight how the extrinsic pathway can be activated
intracellularly in a pathogenic context."
}