LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction

Jay Penney, Kazuya Tsurudome, Edward H. Liao, Grant Kauwe, Lindsay Gray, Akiko Yanagiya, Mario R. Calderon, Nahum Sonenberg and A. Pejmun Haghighi ()
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Jay Penney: McGill University
Kazuya Tsurudome: McGill University
Edward H. Liao: McGill University
Grant Kauwe: Buck Institute for Research on Aging
Lindsay Gray: Buck Institute for Research on Aging
Akiko Yanagiya: Goodman Cancer Research Centre, McGill University, McGill University
Mario R. Calderon: McGill University
Nahum Sonenberg: Goodman Cancer Research Centre, McGill University, McGill University
A. Pejmun Haghighi: McGill University

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Parkinson’s disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.

Date: 2016
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DOI: 10.1038/ncomms12188

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