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.
Highlights
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; we know little about its potential role in the regulation of synaptic plasticity
We find that postsynaptic overexpression of either the fly or the human LRRK2 transgenes can induce a retrograde enhancement of presynaptic release, which is fully reversed by limiting protein translation either genetically or pharmacologically
We found that cap-dependent translation was efficiently enhanced in response to hLRRK2 overexpression; our results indicated that hLRRK2 had only a minimal effect on cap-independent translation, which relies on an internal ribosome entry site (IRES) (Supplementary Fig. 1e)
Summary
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; we know little about its potential role in the regulation of synaptic plasticity. We demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. The details of the molecular steps that lead to triggering this compensatory synaptic enhancement remain unclear; postsynaptic cap-dependent translational mechanisms, under the control of target of rapamycin (TOR), are critical for maintaining this signalling during larval development[4]. Based on the strong link between translational mechanisms and synaptic homeostasis at the Drosophila larval NMJ, we set out to investigate the role of LRRK2 in the regulation of synaptic compensation at the NMJ. We find that postsynaptic overexpression of either the fly (dLRRK) or the human (hLRRK2) LRRK2 transgenes can induce a retrograde enhancement of presynaptic release, which is fully reversed by limiting protein translation either genetically or pharmacologically. Our findings uncover a function for dLRRK in the regulation of synaptic function and suggest that aberrant function of LRRK2 might lead to dysregulation of synaptic function in neural circuits
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