A motif within the armadillo repeat of Parkinson's-linked LRRK2 interacts with FADD to hijack the extrinsic death pathway

Επιστημονική δημοσίευση - Άρθρο Περιοδικού uoadl:3178915 31 Αναγνώσεις

Μονάδα:
Ερευνητικό υλικό ΕΚΠΑ
Τίτλος:
A motif within the armadillo repeat of Parkinson's-linked LRRK2
interacts with FADD to hijack the extrinsic death pathway
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Έτος δημοσίευσης:
2018
Συγγραφείς:
Antoniou, Nasia
Vlachakis, Dimitrios
Memou, Anna
Leandrou,
Emmanouela
Valkimadi, Polytimi-Eleni
Melachroinou, Katerina and
Re, Diane B.
Przedborski, Serge
Dauer, William T.
Stefanis,
Leonidas
Rideout, Hardy J.
Περιοδικό:
Scientific Reports
Εκδότης:
Nature Publishing Group
Τόμος:
8
Επίσημο URL (Εκδότης):
DOI:
10.1038/s41598-018-21931-8
Το ψηφιακό υλικό του τεκμηρίου δεν είναι διαθέσιμο.